Database Release 2023.1

Posted on April 26, 2023 by guidetopharmacology — Leave a comment

The latest release of the IUPHAR/BPS Guide to Pharmacology database was made on 26th April 2023. This database release is version 2023.1, and is the first release this year. The following blog post gives details of the key content updates and website changes. GtoPdb now contains:

  • 3,023 human targets, 1,662 of which have curated quantitative ligand interactions.
  • 11,944 ligands, 8,814 of which have curated quantitative target interactions.
  • 1,872 approved drugs, 1,098 with curated quantitative interactions.
  • Clinical use summaries for over 3,385 ligands of which 1,866 are approved drugs.
  • A total of 19,890 curated binding constants
  • Data curated from over 43,543 references

Curation Update

Updates have been made to many target family summary pages in preparation for generating the 2023-24 issue of the Concise Guide to PHARMACOLOGY (due for publication at the end of the year). More significant modifications have been made to the summary pages for the GABAA receptors (in Ion channels) and Orexin receptors (in GPCRs). A major overhaul of the Taste 2 GPCRs (Bitter taste receptors) has been completed, with newly annotated details for ligands that interact with these receptors. We thank all of our contributors who have given so freely of their time to make these updates possible.

As a regular review of the INN lists from the WHO, we added 31 new kinase inhibitors to the Guide (see table 1), that were included in the Jan 2023 list of proposed INNs (List 128). The chemical structures allowed us to connect around half of these (16/31) INNs to clinical leads (some with declared name>structure), and others to patents from which we could obtain otherwise unpublished target information and interaction data. Five of the structures matched ligands that were already in the Guide. In total we have found interaction data for 27/31 of these inhibitors. For a few, we were unable to track down very little additional information.

31 new kinase inhibitors added to the GtoPdb
Ligand ID INN Name/code Target Ligand ID INN Name/code Target
9131 plixorafenib PLX8394 BRAF 12738 ficonalkib n/a ALK
10094 sofnobrutinib n/a BTK 12379 flizasertib n/a RIPK1
11746 monzosertib AS0141 CDC7 12380 mifanertinib n/a EGFR
12155 zasocitinib NDI-034858 TYK2 12381 resencatinib n/a RET
12319 lartesertib M4076 ATM 12382 risovalisib CYH33 PI3Kα
12357 elenestinib BLU-263 KIT 12383 risvodetinib IkT-148009? Abelson-family tyrosine kinases
12368 boditrectinib AUM601/HL5101 pan-NTRK 12384 rovadicitinib n/a JAK
12369 ifebemtinib BI-853520/IN10018 FAK 12385 tinodasertib AUM001/ETC206 MKNK1/2
12370 lirafugratinib RLY-4008 FGFR 12386 zelasudil n/a ROCK
12371 milrebrutinib AS-1763 BTK 12387 zongertinib BI 1810631? ERBB2
12372 oditrasertib n/a RIPK1 12388 zotizalkib TPX0131 ALK
12373 narmafotinib AMP945 FAK 12389 zurletrectinib n/a NTRK
12374 pumecitinib PG-011? JAK 12390 nimucitinib n/a JAKs
12375 adrixetinib n/a AXL, MER, CSF1R 12391 vabametkib n/a MET
12376 darizmetinib HRX-0215? MKK4 12392 zidesamtinib NVL-520 ROS1
12377 emzeltrectinib n/a NTRK

 

A new set of antivirals for SARS-CoV-2 have been curated, based on patent extractions by our collaborator Chris Southan:

example I-1 [WO2023283831] (12588), TBK845 (12589), example 18 [WO2022013684] (12590), GDI-036 (12591), example 45 [WO2022229458] (12592) and compound 6 [WO2022133588] (12593) are Mpro inhibitors, and PLpro inhibitor 7 (12596) inhibits the other crucial coronavirus protease PLpro. New to this list of antivirals are two PROTAC class protein degraders, both of which target the Mpro for proteosomal degradation; these are CoV Mpro CRBN PROTAC 9 [US11530195] (21594) and CoV Mpro VHL PROTAC 9 [US11518759] (12595).

Keeping up with drug approvals for 2023, there have been 14 new drugs approved by the  FDA since the beginning of the year. The table below provides the ligand IDs for the 11/14 that are curated in the Guide.

14 new drugs approved by FDA in 2023. 11 added to the GtoPdb have ID in first column
Ligand ID INN Trade name Type FDA Approval date Indication EMA approval date
12202 lecanemab Leqembi mAb 06/01/2023 To treat Alzheimer’s disease n/a
12335 bexagliflozin Brenzavvy sm 20/01/2023 To improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise n/a
11628 pirtobrutinib Jaypirca sm 27/01/2023 To treat mantle cell lymphoma n/a
12339 elacestrant Orserdu sm 27/01/2023 To treat advanced/metastatic ER-positive, HER2-negative, ESR1 mutated breast cancer n/a
8455 daprodustat Jesduvroq sm 01/02/2023 To treat anemia caused by chronic kidney disease for adults on dialysis for at least four months n/a
n/a velmanase alfa-tycv Lamzede pep 16/02/2023 To treat non-central nervous system manifestations of alpha-mannosidosis 23/03/2018
8448 sparsentan Filspari sm 17/02/2023 To reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression n/a
n/a efanesoctocog alfa Altuviiio Fc fusion peptide 23/02/2023 Routine prophylaxis and on-demand treatment to control bleeding episodes, as well as perioperative management (surgery) for adults and children with hemophilia A n/a
7573 omaveloxolone Skyclarys sm 28/02/2023 To treat Friedreich’s ataxia in adults and adolescents aged 16 years and older n/a
11513 zavegepant Zavzpret sm 10/03/2023 To treat migraine with or without aura in adults n/a
12482 trofinetide Daybue pep 13/03/2023 To treat Rett syndrome n/a
11583 retifanlimab Zynyz mAb 22/03/2023 To treat metastatic or recurrent locally advanced Merkel cell carcinoma n/a
n/a rezafungin Rezzayo sm 22/03/2023 To treat candidemia and invasive candidiasis n/a
9424 leniolisib Joenja sm 24/03/2023 To treat activated phosphoinositide 3-kinase delta syndrome (APDS) n/a

Antibacterial Curation

We are pleased to report that the Global Antibiotic Research and Development Partnership (GARDP; https://gardp.org/) has extended their funding of our collaboration with Antibiotic DB (ADB; www.antibioticdb.com) for a further 2 years. Through this interaction, GtoPdb provides chemistry and pharmacology for a curated set of antibacterial compounds with links to ADB.

Currently we have 425 ligands tagged in GtoPdb as ‘antibacterial’ and 413 of these have links to compounds at ADB. The antibacterials in the GtoPdb include approved drugs, WHO essential Medicines-listed medicines and a number of investigational and experimental compounds.

Web-Application & Database Update

We have updated the version of ChEMBL used on the website. This is now at ChEMBL version 32. On the Guide to Pharmacology website we use data from ChEMBL to supplement both our pharmacology search and ligand activity charts.

We have updated our PubChem CID outlinks – updating ~380 links some of which had been to deprecated CIDs.

We have also done a check and update of our Ensembl out-links, updating deprecated ID/links in a number of cases.

 

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Posted in Chemical curation, Database updates, Technical

New Cymdeithas Ddysgedig Cymru / Learned Society of Wales Fellows

Posted on April 25, 2023 by guidetopharmacology — Leave a comment

We wish to offer our congratulations to Professor Jamie Davies, Professor of Experimental Anatomy, University of Edinburgh, who has been elected to the Cymdeithas Ddysgedig Cymru/Learned Society of Wales. The society’s new Fellows include academics from across Welsh and UK universities, writers, researchers and leaders from the world of higher education, as well as law, medicine and the media

Jamie has led the IUPHAR/BPS Guide to PHARMACOLOGY database since 2014, having taken over from Professor Tony Harmar, and has been instrumental in the launch of IUPHAR Guide to IMMUNOPHARMACOLOGY and IUPHAR/MMV Guide to Malaria PHARMACOLOGY. Professor Davies said, “I am delighted to be elected, and hope to play my small part in helping to promote the sciences in the land of my birth.”

Also elected to the society is Professor Clare Bryant, Professor of Innate Immunity, Cambridge University. Professor Bryant specialises in the field of innate immunity, which is one of the first lines of defence against antigens, harmful materials, entering the body. This has led to work developing medicines for treating allergies and Alzheimer’s disease. She was also instrumental in supporting the establishment of the IUPHAR Guide to IMMUNOPHARMACOLOGY.

Both Jamie and Clare are 2 of 5 new Fellows elected under the medicine and medical sciences speciality, and you can read more about them here: https://www.learnedsociety.wales/introducing-our-new-fellows-2023-stemm-1-category

Well done Jamie and Clare!

Posted in Guide to Immunopharmacology, Uncategorized

Exploiting the Guide to Pharmacology substance (SID) tags in PubChem

Posted on December 19, 2022 by guidetopharmacology — Leave a comment

This post on SID tagging has been reproduced, with permission, from Dr. Chris Southan’s original post in his blog – Bio <-> Chem. 

It is intended to be user-orientated, those interested in the technicalities are welcome to contact the Guide to Pharmacology curation team. The links and counts in this post we taken on 19th Dec 2022 and reflect data from the 2022.4 GtoPdb release. 

Looking at the tags we have introduced will make this clearer. For starters, as many may know, as of release 2022.4 GtoPdb has 11603 PubChem substance (SID) records. Looking at SID472319339 we can find the following comments.

This includes the explicit tags 

gtopdb_approved – Substance is an approved drug in GtoPdb.

gtopdb_antibacterial – Substance is tagged as an antibacterial in GtoPdb.

So we can employ an interface selection for the gtopdb_approved tag to get 1813  “approved”  (you don’t usually need the [comment] as a field restrict but useful for more complex queries).

Similarly we can select as per below for the 365 antibacterial 

We can then make the requisite intersect via the “Advanced” option on the query interface as below:

The intersection search is thus  (“IUPHAR/BPS Guide to PHARMACOLOGY”[All Fields] AND gtopdb_antibacterial[comment]) AND (“IUPHAR/BPS Guide to PHARMACOLOGY”[All Fields] AND gtopdb_approved[comment])  with the result of 146

We have introduced an additional three selects.  The first is  

gtopdb_immuno – Substance is curated in IUPHAR Guide to Immunopharmacology (GtoImmuPdb) 

with 1384  SIDs as per below:

Cutting the story short we can easily spot the difference between the small-molecule entries that will be subsumed into Compound (CIDs) and the “Structure not Available” entries (two above) that, as large macromolecules, cannot form CIDs and will thus remain  SID-only entries

These are selectable via  our fourth tag  

gtopdb_antibody – GtoPdb identifies this substance as an Antibody 

With which we can select the 335 antibody entries below :

As performed above the intersect below gives the 127  approved antibodies:

Last but not least our fifth tag is 

gtopdb_malaria – Substance is curated in IUPHAR/MMV Guide to Malaria Pharmacology (GtoMPdb)

Which brings back 135 

 

Combining with Venny

Either by combining queries or (much easier) using the query history under the advanced tag we can make any sequence of Boolean selects  (i.e. AND, OR, NOT) from combinations of our five tags for “approved” “immuno” “antibiotic” “antibody” or “antimalarial”.  Below we can see another way of slicing and dicing via Venny.  The example result  shown below compares three of the tag lists we have already looked at. 

One of the useful things with Venny is pull down any intersection lists.  Below is the result of pasting the 70 SIDs from the 3-way intersect back into PubChem (the interface can take fairly large lists). 
 

Another advantage of these GtoPdb specific retrievals is to be able to pivot across to small molecule CIDs. The steps to do this are shown below, highlighted in yellow.

The result below, transformed into a PubChem compound query,  now retrieves all CIDs that include GtoPdb approved  SIDs

Thus GtoPdb contains 1586 approved drug CIDs.  Note that not all these are strictly “small molecules as we can see from the Mw ranking below where the top-ten are above 5000 Mw

Posted in Chemical curation, Technical, Tutorials and Guides

Database Release 2022.4

Posted on December 13, 2022 by guidetopharmacology — 1 Comment

The latest release of the IUPHAR/BPS Guide to Pharmacology database was made on 13th December 2022. This database release is version 2022.4, and is the fourth release this year. GtoPdb now contains:

  • 3,013  human targets, 1,633 of which have curated quantitative ligand interactions.
  • 11,596 ligands, 8,557 of which have curated quantitative target interactions.
  • 1,813 approved drugs, 1,071 with curated quantitative interactions.
  • Clinical use summaries for over 3,267 ligands of which 1,806 are approved drugs.

Website Updates

Our PostgreSQL version has been update to 12.13.

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Hot Topics: FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Posted on December 7, 2022 by guidetopharmacology — Leave a comment

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

This manuscript (1) reports on extensive and compelling experimental evidence and translational data from retrospective review of clinical registries, which show that pharmacological inhibition of the farnesoid X receptor (FXR) could be a novel intervention for the prevention or treatment of COVID-19. The in vitro and in vivo studies show that FXR antagonism reduces ACE2 expression, which subsequently reduces SARS-CoV-2 infection in the lung, liver and gastrointestinal tract.

  1. Brevini T, Maes M, Webb GJ, John BV, Fuchs CD, Buescher G, Wang L, Griffiths C, Brown ML, Scott WE 3rd, Pereyra-Gerber P, Gelson WTH, Brown S, Dillon S, Muraro D, Sharp J, Neary M, Box H, Tatham L, Stewart J, Curley P, Pertinez H, Forrest S, Mlcochova P, Varankar SS, Darvish-Damavandi M, Mulcahy VL, Kuc RE, Williams TL, Heslop JA, Rossetti D, Tysoe OC, Galanakis V, Vila-Gonzalez M, Crozier TWM, Bargehr J, Sinha S, Upponi SS, Fear C, Swift L, Saeb-Parsy K, Davies SE, Wester A, Hagström H, Melum E, Clements D, Humphreys P, Herriott J, Kijak E, Cox H, Bramwell C, Valentijn A, Illingworth CJR; UK-PBC research consortium, Dahman B, Bastaich DR, Ferreira RD, Marjot T, Barnes E, Moon AM, Barritt AS 4th, Gupta RK, Baker S, Davenport AP, Corbett G, Gorgoulis VG, Buczacki SJA, Lee JH, Matheson NJ, Trauner M, Fisher AJ, Gibbs P, Butler AJ, Watson CJE, Mells GF, Dougan G, Owen A, Lohse AW, Vallier L, Sampaziotis F. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature. 2022 Dec 5. doi: 10.1038/s41586-022-05594-0. Epub ahead of print. PMID: 36470304.

Comments by the Guide to Pharmacology Curation Team, University of Edinburgh

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Database Release 2022.3

Posted on October 13, 2022 by guidetopharmacology — Leave a comment

The latest release of the IUPHAR/BPS Guide to Pharmacology database was made on 13th October 2022. This database release is version 2022.3, and is the third release this year. The following blog post gives details of the key content updates and website changes. GtoPdb now contains:

  • 3,007 human targets, 1,627 of which have curated quantitative ligand interactions.
  • 11,532 ligands, 8,517 of which have curated quantitative target interactions.
  • 1,782 approved drugs, 1,057 with curated quantitative interactions.
  • Clinical use summaries for over 3,227 ligands of which 1,774 are approved drugs.

New ligands

For this release we can announce the inclusion of new ligand entries for chemical structures that have been revealed during recent ‘first disclosure’ sessions at scientific conferences. For those structures that meet our inclusion criteria, we have curated details of any clinical studies, or intended therapeutic use for these new entries, and included quantitative interaction data where we have been able to find it, as well as any source references.

ACS, Chicago Aug 2022
Name Ligand ID MMOA
evixapodlin/GS-4224 11684 oral small molecule PD-L1 inhib
compound 17 12152 oral MRGPRX2 antagonist
FLX475 12153 oral CCR4 antagonist
mitiperstat/AZD4831 12154 MPO inhibitor
NDI-034858 12155 TYK2-selective kinase inhibitor
onfasprodil 12156 NR2B (GluN2B; GRIN2B)-selective negative allosteric modulator
GLPG3970 12157 SIK2/3 inhibitor
PF-07258669 12158 MC4R antagonist
EFMC-ISMC, Nice Sep 2022
vicasinabin/RG7774 11890 oral CB2R agonist
compound 22 [WO2019141694A1] 12181 inhaled PI4KB inhibitor

New COVID-19 drug targets

2 new targets have been added, including interactions with small molecule modulators:

A host enzyme: phosphodiesterase 12 (PDE12); Two tool compounds have been added, compound 1 [PMID: 26055709] and compound 3 [PMID: 26055709], and we are awaiting disclosure of two lead compound structures that were reported in a bioRxiv preprint in Sept 2022 https://www.biorxiv.org/content/10.1101/2022.09.23.509178v1.full

A coronavirus protein: Non-structural protein 15 (aka endoribonuclease NendoU). Two allosteric inhibitors have been reported, FUZS-5 (Ligand ID 12200) and LIZA-7 (Ligand ID 12199). The docking positions of these compounds within nsp15 have been determined by X-ray crystallography https://www.biorxiv.org/content/10.1101/2022.09.26.509485v1. We have included tipiracil (8696) in the inhibitors table as it has also demonstrated some activity against SARS-CoV-2 nsp15.

Antibacterial Ligands

As part of our continuing collaboration with AntibioticDB and GARDP we now have 351 curated antibacterial ligands in the Guide to PHARMACOLOGY.

Website Updates

Our chemical structure search now uses the Chemistry Development Kit (CDK) to power the similarity search. The Chemistry Development Kit (CDK) is a collection of free and open-source modular Java libraries for processing chemical information.

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Database Release 2022.2

Posted on June 9, 2022 by guidetopharmacology — Leave a comment

A new database release (version 2022.2) of the IUPHAR/BPS Guide to Pharmacology was made on 9th June 2022. This blog post gives details of the key content updates and website changes. GtoPdb now contains:

  • 3,002 human targets, 1,611 of which have curated quantitative ligand interactions.
  • 11,348 ligands, 8,396 of which have curated quantitative target interactions.
  • 1,756 approved drugs, 1,052 with curated quantitative interactions.
  • Clinical use summaries for over 3,146 ligands of which 1,752 are approved drugs.

New targets and their interactions with newly curated ligands

Selectin E (OID 3200) and a selective antagonist uproleselan (LID 11995): Selectin E is a vascular adhesion molecule present on the endothelial cell surface that is involved in leukocyte migration and in cancer cell trafficking (especially metastasis). Uproleselan-mediated antagonism of selectin E binding is being investigated for anti-cancer potential and has been repositioned for anti-inflammatory action in patients with severe COVID-19 pneumonia (predicted to reduce leukocyte recruitment to the inflamed lungs).

Palmitoyl-protein thioesterase 1 (OID 3199) and the inhibitor ezurpimtrostat (LID 11991): Ezurpimtrostat (GNS561) is a small molecule inhibitor of palmitoyl-protein thioesterase 1 (PPT1). It induces lysosomal dysregulation which leads to inhibition of late-stage autophagy and cell death. Antitumour and antiviral activities have been demonstrated in vitro and in vivo. Anti-SARS-CoV-2 activity is being investigated in Phase 2 clinical trial NCT04637828.

CoV Non-structural protein 14 (nsp14 OID 3198) has been added as a separate entry in the Coronavirus (CoV) proteins family to allow effective curation of nsp14 inhibitors. The methyltransferase (MTase) activity of nsp14 is required for capping of the viral RNA transcript. Inhibition of this activity should disrupt viral replication. Two experimental inhibitors have been curated, TO507 (LID 11981) and compound 25 [PMID: 35439007] (LID 11971).

New ligands

We have added those ligands from the DrugHunter ‘Molecules of the month’ sets for April and May that were absent from our curated ligands. Of the total April/May combined set of 18 compounds, we had already included 5 through our own curation efforts, and added 11 as new entries. We did not add branaplam (a RNA-targeted splicing modulator for spinal muscular atrophy and/or Huntington’s disease) as it doesn’t act via a defined protein target, and we didn’t add the HIV-1 protease inhibitor ‘compound 14’ as we currently don’t include HIV proteins as ligand/drug targets.

SARS-CoV-2/COVID-19 related ligands for coronavirus page- new and updates to existing entries

We reviewed the compounds in current COVID-19 clinical trials (from clinicaltrials.gov) to identify agents (particularly small molecule compounds) that either didn’t exist in the GtoPdb or which needed updated curation wrt clinical potential as antivirals or treatments for symptomatic COVID-19. The results include:

New FDA drug approvals

In May, the FDA approved 3 drugs that are ‘first-in-class’ therapeutics. In date order of approval these are:

  • Vonoprazan (LID 11549) is the first potassium competitive acid blocker (PCAB) class drug to be FDA approved. Its interaction with the gastric proton pump (H+,K+-ATPase) is reversible, so it offers advantages over the existing irreversible proton pump inhibitors (PPIs). Tegoprazan and revaprazan are two additional PCABs that are authorised for clinical use in South Korea.
  • Tapinarof is the first aryl hydrocarbon receptor (AhR) agonist to enter clinical use. It is indicated for the treatment of psoriasis, and provides a number of advantages compared to standard corticosteroid treatments, particularly in respect of side-effects and long-term use.
  • Tirzepatide is the first in its class of dual acting glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonists (‘twincretin’). The FDA approved it for T2DM management. Recently published Phase 3 results from the SURMOUNT-1 study (NCT04184622) demonstrate that this dual agonist approach also produces significant and sustained weight reduction in obese patients [PMID:35658024].
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Prof. Jamie Davies – RSE Fellow

Posted on May 31, 2022 by guidetopharmacology — Leave a comment

Congratulations to Professor Jamie Davies, Professor of Experimental Anatomy, University of Edinburgh, who has been elected to a Fellowship by The Royal Society of Edinburgh, Scotland’s National Academy.

Fellowships are awarded to individuals  in academia, business and public service who are judged to be eminently distinguished in their subject.

Jamie has led the IUPHAR/BPS Guide to PHARMACOLOGY database since 2014, having taken over from Professor Tony Harmar (also a Fellow of the Society), and has been instrumental in the launch of  IUPHAR Guide to IMMUNOPHARMACOLOGY and IUPHAR/MMV Guide to Malaria PHARMACOLOGY.

 

Posted in Database updates, Events, Guide to Immunopharmacology, Guide to Malaria Pharmacology

Hot Topics: A new study shows that human ageing is absolutely precise, when disease is eliminated, and accompanied by a disintegration of metabolic efficiency

Posted on April 13, 2022 by guidetopharmacology — Leave a comment

Human ageing is just disintegration, but absolutely precise, linked to loss of VO2 max, which is why COVID is age-related.

A new study (1) shows that the decline in human performance with age at 5000 m, an athletic event requiring high VO2 max (oxygen use), is remarkably precise, and unavoidable, and related to entropy, even at an individual level. Women and men show an identical age-related decline, up to ~100 years old. The precision of the decline shows the limitations for therapy of aging. Mortality incidence for COVID19 shows a similar relationship. The authors propose that initial VO2 max has a critical role in COVID sensitivity because of the direct relationship of disease severity with oxygen use, and the parallel decline in aging: mitochondria are targeted by viruses. The highest human recorded VO2 max is 96, but is only 13 in nursing home residents, where metabolic capacity is massively reduced.

Humans, with a long active life, may therefore have already optimised ageing and metabolism (2) compared to short-lived animals which are used in studies of anti-ageing drugs.

As the results involve the very best age-related performances of humanity (by definition healthy), and there is absolute mathematical precision in the decline, there is no room for improvement, so drugs to slow ageing (apart from offsetting specific ageing-related diseases) may well remain a mirage. The results of the study are compatible with decline due to entropy, just a general disintegration, with different diseases developing by chance, heredity or the environment in a disintegrating body.

Funding could be better spent on ensuring a humane and dignified exit at the end of life when metabolism breaks down completely. Nevertheless, exercise (such as 5000M parkruns) has been previously shown to extend active life by ~7 years (3).

  1. Spedding M, Marvaud R, Marck A, Delarochelambert Q, Toussaint JF. Aging, VO2 max, entropy, and COVID-19. Indian J Pharmacol 2022;54:58-62. https://www.ijp-online.com/text.asp?2022/54/1/58/339909. PMID: 35343209.
  2. Bozek K, Wei Y, Yan Z, Liu X, Xiong J, Sugimoto M, Tomita M, Pääbo S, Pieszek R, Sherwood CC, Hof PR, Ely JJ, Steinhauser D, Willmitzer L, Bangsbo J, Hansson O, Call J, Giavalisco P, Khaitovich P. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness. PLoS Biol. 2014 May 27;12(5):e1001871. doi: 10.1371/journal.pbio.1001871. PMID: 24866127.
  3. Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, Santos-Lozano A, Fiuza-Luces C, Morán M, Emanuele E, Joyner MJ, Lucia A. Exercise attenuates the major hallmarks of aging. Rejuvenation Res. 2015 Feb;18(1):57-89. doi: 10.1089/rej.2014.1623. PMID: 25431878.

Comments by the Guide to Pharmacology Curation Team, University of Edinburgh

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Hot Topics: Endothelin-1 pathway, a new therapeutic target for COVID-19

Posted on April 12, 2022 by guidetopharmacology — Leave a comment

SARS-CoV-2 gains entry into the body mainly via the lungs. After entering the blood, the virus rapidly multiplies to infect nearby cells. Endothelial cells line every blood vessel and have a surface area similar to a tennis court. These cells are especially vulnerable to virus infection as they express the the virus entry receptor, ACE2. Endothelial cells are also a source of endothelin-1 (ET-1), which is released in response to injury to cause long lasting vasoconstriction, reducing oxygen supply to vital organs. In the lungs, this can cause breathing difficulty, which in severe cases requires patients to be given oxygen and put on a ventilator.

The study compared ET-1 in the plasma of patients infected with COVID-19 who were hospitalised during the first wave of the pandemic, including those placed on ventilators (1). Significantly higher levels of ET-1 were measured in these patients, compared with infected individuals with mild or no symptoms. The release of multiple copies of the virus following infection is known to damage endothelial cells and the results show stored ET-1 is also released into the bloodstream.

Currently, medicines that block the detrimental actions of ET-1 are used to treat rare forms of lung disease that share some of the clinical features of COVID-19 infection. The results provide evidence to support testing these medicines in clinical trials to see if they would benefit the most severely affected patients. The virus continues to evolve and in addition to vaccines and bespoke antivirals, that may be susceptible to the development of resistance, it is important to develop alternative ways to block the harmful actions of the virus. By targeting the damaging actions of SARS-CoV-2 on the host cells, medicines are likely to remain effective irrespective of evolving mutations in the virus.

  1. Abraham GR, Kuc RE, Althage M, Greasley PJ, Ambery P, Maguire JJ, Wilkinson IB, Hoole SP, Cheriyan J, Davenport AP. Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. J Mol Cell Cardiol. 2022 Mar 23:S0022-2828(22)00051-7. doi: 10.1016/j.yjmcc.2022.03.007. PMID: 35339512.

Comments by the Guide to Pharmacology Curation Team, University of Edinburgh

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Database Release 2022.1

Posted on March 31, 2022 by guidetopharmacology — Leave a comment

We are pleased to announce that the first IUPHAR/BPS Guide to Pharmacology of 2022 was made on 31st March 2022. database. This release is version 2022.1 and this blog post gives details of the key content updates and website changes. GtoPdb now contains:

  • 3,000 human targets, 1,607 of which with curated quantitative ligand interactions.
  • 11,270 ligands, 8,349 of which have curated quantitative target interactions.
  • 1,734 approved drugs, 1,044 with curated quantitative interactions.
  • Clinical use summaries for over 3,093 ligands of which 1,730 are approved drugs.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

Notable additions and updates for this period include:

Baricitinib – In March 2022, data reported from the largest of the baricitinib studies (part of the University of Oxford-led RECOVERY trial) indicated that it provided clinical benefit in hospitalised COVID-19 patients, including in those already receiving other standard care immunomodulatory treatments (e.g.dexamethasone, tocilizumab) or the antiviral drug remdesivir. This made baricitinib the 4th effective COVID-19 therapy to be identified by the RECOVERY trial.

N-0385  – A serine protease inhibitor, that was originally reported as a matriptase inhibitor. More recently revealed to inhibit SARS-CoV-2 infection via inhibition of TMPRSS2 (the host protease hijacked by the coronavirus to cleave spike and facilitate entry into host cells), thus functioning as an ‘entry inhibitor’. The Nature article (DOI: 10.1038/s41586-022-04661-w) proposes prophylactic and therapeutic potential, as well as pan-coronavirus efficacy that is independent of virus strain. May have applications in combination with antivirals with other MMOAs e.g. Mpro (nirmatrelvir) or RdRp (e.g. molnupiravir, remdesivir) inhibitors.

Curation Updates

2021.4 update we have added 131 new ligands. We have also made updates to ~38 existing ligand comments and ~28 clinical use comments. An additional 10 existing ligand have now been tagged as approved drugs, bringing the total approved drugs in GtoPdb to 1,730.

All new ligands have been manually curated with chemical or peptide structures, links to external resources, general comments, notes on clinical development where appropriate,  target interaction data and patent pointers where available. Two particular sets are from recent collaborative blogposts. The first consisted of six  DrugHunter compounds from Feb 2022.  The second set of six was the popular ACS First Disclosures from their March spring meeting (see BLU945 below).  For most of these fresh drug discovery ligands (some of which are patent-only and not yet published) we will be the first source to provide name-to-structure matches both in our own database and in PubChem (including PubChem < > PubMed links).

A few new interesting ligands are:

  • YCT529 – Oral retinoic acid receptor alpha (RAR-α) antagonist, that is being investigated as a non-hormonal male contraceptive. Its development and function were presented at the spring meeting of the American Chemical Society (ACS) in March 2022 (but not as a First Disclosure).  Antagonising RAR-α disrupts spermatogenesis. YCT529 is formulated as a sodium salt. It exerts the expected in vivo effect on sperm development. The RAR-α-selective antagonists BMS-189532, BMS-189614 and and BMS-189532 have been reported previously (PMID: 24040487, PMID: 32671394).
  • BLU945 – A fourth generation non-covalent, and orally available EGFR inhibitor, that was designed to inhibit the EGFR pathway and provide anti-tumour activity in NSCLC with EGFR resistance mutations (EGFR with triple mutations) that block sensitivity to the 3rd generation EGFR inhibitor osimertinib.
  • compound 17b [PMID: 35286086] – A gefitinib–tamoxifen hybrid molecule, that was developed to combat triple-negative breast cancer. It simultaneously targets both estrogen receptor and epidermal growth factor receptor (EGFR) pathways to block cancer cell growth.

New Targets

Whilst no new targets have been added to the database for this release we want to draw attention to the set of novel protein targets for drugs that were approved by the FDA (US), EMA (EU) and/or PMDA (Japan) in 2021. 14 targets of the 2021 approved drugs set are novel, and 9 of these 14 are indicated for rare diseases*. Links to our pages for these targets and drugs (where available) are provided in the table below :

Target Approved drug Drug class Indication
Angiopoietin-related protein 3 (ANGPTL3) evinacumab* mAb Homozygous familial hypercholesterolaemia
Thymic stromal lymphopoietin (TSLP) tezepelumab mAb Severe asthma
Interleukin-17F (IL17F) bimekizumab mAb Psoriasis
Interleukin-13 (IL13) tralokinumab mAb Atopic dermatitis
Neonatal Fc receptor (FCGRT) efgartigimod alfa* mAb Myasthenia gravis
SARS-CoV-2 Spike protein regdanvimab, sotrovimab, casirivimab, imdevimab mAb COVID-19
Tissue factor (TF) tisotumab vedotin mAb-ADC Cervical cancer
Transferrin receptor protein 1 (TFRC) pabinafusp alfa* Fusion protein Hunter syndrome
Molybdenum cofactor biosynthesis protein 1 (MOCS1) fosdenopterin* Synthetic substrate Molybdenum cofactor deficiency type A
Natriuretic peptide receptor 2 (NPR2) a.k.a. Guanylyl cyclase-B vosoritide* Peptide Achondroplasia
Complement C3 (C3) pegcetacoplan* Peptide Paroxysmal nocturnal hemoglobinuria
CMV serine/threonine protein kinase UL97 (UL97) maribavir* Small-molecule (inhibitor) Post-transplant CMV infection/disease
GTPase KRas (KRAS) sotorasib* Small-molecule (inhibitor) Non-small-cell lung cancer
Hypoxia-inducible factor 2 alpha (HIF2α) belzutifan* Small-molecule (inhibitor) von Hippel–Lindau disease

Website Updates

  • Our download files now have an comment line added at the top which indicated the database version number and release date. This line is preceded by a double-hash ‘##’. We ask user to take note of this as it may have an impact on any existing downstream processing that users conduct.
  • Our targets and families download file has been update to contain Ensembl Gene IDs.

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

The Antimalarial targets family and the Antimalarial ligands family have been updated, giving a total of 40 P. falciparum (3D7) targets and 134 ligands tagged as antimalarial in the database. Work has continued on the process of adding subfamilies to the Antimalarial targets family.

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Hot Topics: SARS-CoV-2 and the truncated ACE-2 variant

Posted on February 6, 2022 by guidetopharmacology — Leave a comment

ACE2 (Guide to Pharmacology Target id: 1614) normally functions as an enzyme metabolising peptides that regulate the cardiovascular system. As is well known though, it has recently gained additional scientific fame by also acting as a receptor for SARS-CoV-2. This study [1] compared the distribution in human tissue of ACE2 versus deltaACE2, a recently discovered truncated isoform that has lost the spike binding sites  for SARS-CoV-2, and is predicted to confer reduced susceptibility to viral infection. ACE2 was highly expressed in human lung, kidney, heart, liver and vasculature. However, deltaACE2 was the predominant protein alternative initiation variant in lung airway and liver bile duct epithelia, which may be a contributing factor to variation in response to the virus. A diagrammatic relationships of the full length and dACE is shown below.

The discovery of this novel short dACE2 variant in two independent reports may have important implications in COVID-19 research. It is enzymatically inactive, and the absence of the spike binding domains of the full-length ACE2 suggests dACE2 does not bind SARS-CoV-2 spike protein. It is still unclear what the precise effects of such an alternative form are in both normal physiology and in relation to SARS-CoV-2 infection and Long COVID, but the ratio of dACE2 versus the full-length protein may be a contributing factor in the wide inter-individual variation in response to COVID-19

  1. Williams TL, Strachan G, Macrae RGC, Kuc RE, Nyimanu D, Paterson AL, Sinha S, Maguire JJ, and Davenport AP. Differential expression in humans of the viral entry receptor ACE2 compared with the short deltaACE2 isoform lacking SARS-CoV-2 binding sites. Sci Rep. 11:24336. (2021). [PMID: 34934117]

Contributed by Christopher Southan, ORCID 0000-0001-9580-0446, Data Science, Medicines Discovery Catapult and Honorary Fellow, University of Edinburgh

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Database Release 2021.4

Posted on December 14, 2021 by guidetopharmacology — 1 Comment

The 2021.4 release of the IUPHAR Guide to Pharmacology was made on 14th December 2021. This blog post gives details of the key content updates and website change The 2021.4 release contains:

  • 3,000 human targets with curated quantitative ligand interactions.
  • 11,139 ligands, 8,240 of which have curated quantitative target interactions.
  • 1,717 approved drugs, 1,033 with curated quantitative interactions.
  • Clinical use summaries for over 3,052 ligands of which 1,713 are approved drugs.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

Updates have most notably been made to the comments for molnupiravir (EIDD-2801, MK-4482). This followed its MHRA approval on 4th Nov 2021 as a treatment or recently diagnosed SARS-CoV-2 infection in non-hospitalised individuals who have at least one risk factor for developing severe illness.

Also add to the ligand list is PF-07321332, an oral SARS-CoV-2 3CL protease (Mpro) inhibitor, and clinical lead compound from Pfizer. It was progressed to clinical trial to determine safety and efficacy as a treatment for COVID-19. Phase 1 (NCT04756531) results were published in Science, in early November 2021 DOI: 10.1126/science.abl4784. A few days after the Phase 1 results were published, Pfizer announced that interim analysis from their Phase 3 EPIC-HR study (NCT04960202), indicated that PF-07321332 (in combination with ritonavir, as a formulation with the trade name Paxlovid) reduced the risk of hospitalisation or death by almost 90% in patients who were at high risk of progressing to severe illness, and who were treated within 3 days of symptom onset https://bit.ly/3wxA5of.

OAS1 (HGNC:8086; UniProt: P00973), an interferon-induced gene that is part of the innate antiviral defence system within host cells, has been added to the target table.

Curation Updates

Since our 2021.3 update we have added over ~110 new ligands. These have all been manually curated with chemical or peptide structures, links to external resources, general comments, notes on clinical development where appropriate, and target interaction data where this is available.

We have also made updates to ~46 existing ligand comments and ~52 clinical use comments. An additional 18 existing ligand have now been tagged as approved drugs, bringing the total approved drugs in GtoPdb to 1,716.

New Targets

5 new targets have been added to the database since the last release. These include HtrA serine peptidase 1, the target of galegenimab (Ph 2 geographic atrophy); heat shock protein family A (Hsp70) member 5, a potential therapeutic target for viral infections (incl. SARS-CoV-2), chemoresistant cancers and inflammation; coagulation factor III, tissue factor, the target of tisotumab vedotin (approved, oncology);clusterin: the target of sotevtamab (Ph 2 immunomodulator, antineoplastic); and transferrin receptor (CD71), which is exploited to improve site-specific drug delivery, including drug delivery across the blood-brain barrier e.g. pabinafusp alfa, lepunafusp alfa that deliver enzymes that are deficient in lysosomal storage disorders (both approved in Japan).

Website Updates

  • The Guide to PHARMACOLOGY home-page has been revised, giving priority to the ways users can access the data. The site search and links to advanced search tools are more prominent. New panels link to ligand activity graphs, GtoImmuPdb, GtoMPdb, and current key resources. Page elements are more condensed to the top of the page and the site banner has been updated. 
new GtoPdb home page

Screenshot of the new GtoPdb home page. The site search is now more prominent, alongside the more advance search tools.

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

Posted in Database updates, Guide to Malaria Pharmacology

Hidden REF award to Guide to Pharmacology

Posted on October 11, 2021 by guidetopharmacology — Leave a comment

It is with great pleasure that we can announce that the  IUPHAR/BPS Guide to PHARMACOLOGY has been given a hidden REF award in the category ‘applications of research’.

Guide to Pharmacology hidden REF certificate

The hidden Ref (https://hidden-ref.org) is a national ‘competition’, supported by publishers, learned societies etc. (https://hidden-ref.org/supporters/) , designed to celebrate and recognise the range of important research achievements that may not fit neatly into a REF submission.

“The ways in which the research impact is judged overlooks many of the people who are vital to the success of research. It’s only by recognising everyone who is vital to the conduct of research that we will create an environment in which to advance it.”

We are of course very grateful to receive this award, and our thanks go to the hidden REF committees.

Being recognised in this way is a testament to the hard work of the entire Guide to PHARMACOLOGY team, both past and present, who’s vision and dedication has provided the research community with such an invaluable resource.

The award ceremony is available to view and you can watch the specific announcement of the GtoPdb award in the following video (starts ~10 mins in):

More information on the hidden REF is provide in this video:

 

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Database Release 2021.3

Posted on September 2, 2021 by guidetopharmacology — 1 Comment

The new release of the IUPHAR Guide to Pharmacology was made on 2nd September 2021 – this is version 2021.3. This blog post gives details of the key content updates and website changes.

The 2021.3 release contains:

  • 1,596 human targets with curated quantitative ligand interactions.
  • 11,025 ligands, 8,161 of which have curated quantitative target interactions.
  • 1,688 approved drugs, 1,018 with curated quantitative interactions.
  • Clinical use summaries for over 3,005 ligands of which 1,684 are approved drugs.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19. 

Most recently we have added the DX600 experimental peptide, which has been shown to prevent pseudotyped SARS-CoV-2 from entering heart cells (Williams et al., Commun. Biol, 2021). Also added are two monoclonal antibody cocktails. The first, AZD7442, is a combination of cilgavimab and tixagevimab, which reach phase 3 clinical evalutaion, and is proposed to have therapeutic potential in treating individuals who respond poorly to vaccination. The second, Ronapreve, is a combination of imdevimab and casirivimab, aimed at blocking SARS-CoV-2 entry into cells it was approved by the UK’s MHRA in August 2021 having previous been approved by both the FDA and Japanese Ministry of Health.

Curation Updates

Since our 2021.2 update we have added over ~120 new ligands. These have all been manually curated with chemical or peptide structures, links to external resources, general comments, notes on clinical development where appropriate, and target interaction data where this is available.

We have also made updates to over 170 existing ligand comments and 102 bioactivity comments. An additional 8 existing ligand have now been tagged as approved drugs, bringing the total approved drugs in GtoPdb to 1,688.

Website Updates

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

 

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Hot Topics: Trends in kinase drug discovery: twenty years of successfully targeting the kinome

Posted on August 6, 2021 by guidetopharmacology — Leave a comment

The FDA approval of imatinib in 2001 was a breakthrough in molecularly targeted cancer therapy and heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. Continued advances in the molecular understanding of cancer, multiple approaches to drug design, and the increasing number of resolved kinase structures (1) have facilitated the development of kinase inhibitors with improved potency, selectivity, and efficacy.

Two new analyses published in Nature Reviews Drug Discovery present the historical development of kinase inhibitors as well as the current outlook on kinase drug discovery. Cohen et al. (1) present a detailed study on FDA-approved small molecular weight kinase inhibitors titled Kinase drug discovery 20 years after imatinib: progress and future directions. The analysis encompasses the pivotal events in kinase inhibitor development and remarkable progress made over the past 20 years in improving the potency and specificity of small molecule kinase inhibitors (SMKIs) and the kinase pathways targeted in drug discovery. Importantly, the development of drug resistance to kinase inhibitors and how these challenges are being met in the future of kinase drug discovery are discussed.

The new analysis Trends in kinase drug discovery: targets, indications and inhibitor design published this month by Attwood et al. (2) analyses the landscape of approved and investigational therapies targeting kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. Furthermore, strategies for kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors, and chemical degraders are discussed. Since the approval of fasudil in 1995, the number of approved kinase inhibitors worldwide as increased to 98 drugs, of which 71 are SMKIs and 10 monoclonal antibodies approved by the FDA. Remarkably, the number of FDA-approved SMKIs has more than doubled in the past five years and they constitute ~15% of all novel drug approvals by the FDA. While oncology is still the predominant area for their application, there have been important approvals for indications such as rheumatoid arthritis, and one-third of the SMKIs in clinical development address disorders beyond oncology. Nearly 600 investigational kinase-targeting agents that were registered in ClinicalTrials.gov were included this analysis, consisting of 475 novel SMKIs and 124 biological agents. Information on clinical trials of SMKIs reveals that ~110 novel kinases are currently being explored as targets, which together with the ~45 targets of approved kinase inhibitors represent only ~30% of the human kinome (4), indicating that there are still substantial unexplored opportunities for this drug class.

In summary, although there have been substantial advances in kinase drug discovery, there are still many challenges and opportunities in this field. The potential for developing novel types of kinase inhibitors is large and it is expected that this will continue to be a major area of growth in the next 20 years.

Comments by Misty Attwood and Helgi Schiöth, University of Uppsala, Uppsala, Sweden. Helgi Schiöth is Chair for NC-IUPHAR Subcommitees for Melanocortin receptors and Prolactin-releasing peptide receptor. Twitter: @FunctPharm

  1. Structural Genomics Consortium (SGC): https://www.thesgc.org/.
  2. Cohen, P., Cross, D. & Jänne, P.A. Kinase drug discovery 20 years after imatinib: progress and future directions. Nat Rev Drug Discov 20, 551–569 (2021). [PMID: 34002056]
  3. Attwood, M. M., Fabbro, D., Sokolov, A. V., Knapp, S., Schiöth, H. B. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. In press (2021). [PMID: 34354255]
  4. IUPHAR Guide to Pharmacology: https://www.guidetopharmacology.org.

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Database Release 2021.2

Posted on June 25, 2021 by guidetopharmacology — Leave a comment

The new release of the IUPHAR Guide to Pharmacology was made on 25th June 2021 – this is version 2020.2. This blog post gives details of the key content updates and website changes.

The 2021.2 release contains:

  • 1,588 human targets with curated quantitative ligand interactions.
  • 10,894 ligands, 8,066 of which have curated quantitative target interactions.
  • 1,664 approved drugs, 1,006 with curated quantitative interactions.
  • Clinical use summaries for over 2,934 ligands of which 1,660 are approved drugs.

Curation Updates

Since our 2021.2 update we have added over 70 new ligands. These have all been manually curated with chemical or peptide structures, links to external resources, general comments, notes on clinical development where appropriate, and target interaction data where this is available. We have also made update to over 40 existing ligand comments and clinical use summaries. Bioactivity comments have been updated on 10 ligands and 16 existing ligand have now been tagged as approved drugs.

Website Updates

  • New homepage (beta version) is available. This is a minor re-working of our homepage to prioritise the database search tools and access to ligand activity charts, immunopharmacology and malaria pharmacology. 
  • Added links from solute-carrier targets to the RESOLUTE – Solute Carrier Knowledgebase

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

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Database Release 2021.1

Posted on March 18, 2021 by guidetopharmacology — Leave a comment

Here are the details for the first release in 2021 of the Guide to PHARMACOLOGY database, version 2021.1. This is the last release before we move forward with the process of preparing the next edition of the Concise Guide to Pharmacology (2021/22). As such, the release contains many updates specifically with the CGTP in mind.

The 2021.1 release contains:

  • 1,580 human targets with curated quantitative ligand interactions.
  • 10,821 ligands, 8,016 of which have curated quantitative target interactions.
  • 1,643 approved drugs, 995 with curated quantitative interactions.
  • Clinical use summaries for over 2,899 ligands of which 1,639 are approved drugs.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

The peptide GM-CSF has been added to the targets lists as this has been indicated as a principal marker of sever COVID-19 immunopathology. Ligands added in include ensovibep (MP0420), emovododstat & MK-7110. Updates made to comments for sarliumab and tocilizumab.

Curation Updates

There have been some fairly significant updates in this release as a precursor to preparing the 2021/22 edition of the Concise Guide to Pharmacology.

A new family of enzymes, Peptidyl-prolyl cis/trans isomerases (PPIases), has been added. This includes some of the best understood PPIases, in particular those that are therapeutic targets (current or under investigation). We have added several pharmacological modulators that can be used to investigate their biological roles, as well as relevant clinical candidate compounds.

Ten of our ligands have been updated to reflect their approval by the FDA in the first quarter of 2021: vericiguat, cabotegravir, voclosporin, tepotinib, umbralisib, evinacumab-dgnb, trilaciclib, casimersen, serdexmethylphenidate and tivozanib.

Since our 2020.5 update we have added 220 new ligands. These have all been manually curated with chemical or peptide structures, links to external resources, general comments, notes on clinical development where appropriate, and target interaction data where this is available.

Many of our target family summary pages have been reviewed by our expert committees, and revised in preparation for generating the next edition of the Concise Guide to PHARMACOLOGY (2021/22 ed).

Website Updates

  • New ligand ID mapping file is available from downalods. This mapps GtoPdb ligand IDs to other database identifiers (inc. PubChem CID/SID, ChEMBL, ChEBI, UniProt, DrugBank and DrugCentral)
  • Also a new download file that provide all GtoPdb ligands, with structures, as a SDF (structure-data file).
  • Links from ligand summary pages to Reactome reactions and drug entities
  • Minor fixes to family tree-hierarchy display to hide expand/collapse buttons if there are no nodes to expand.
  • Update to RCSB PDB ligand links (updated URL)
  • New home page (beta version) is accessible here https://www.guidetopharmacology.org/index_beta.jsp

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

screenshot-2021-02-25-at-18.39.57Figure 1. The Antimalarial targets family page illustrating the new subfamily classification (highlighted in magenta).

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GtoPdb pre-release ligands (2021.1)

Posted on February 1, 2021 by guidetopharmacology — Leave a comment

These are some of the ligands under curation (pre-release) in the Guide to Pharmacology. We expect them to be available on the website at the next database release (2021.1).

Ligand ID: 11395
Names: MK-7110
Comment: MK-7110 (originally OncoImmune’s CD24Fc) is a synthetic protein that fuses the nonpolymorphic regions of CD24 (which is an agonist of Siglec-10) to the Fc region of human IgG1 [PubMed ID:19264983]. It.is being investigated as a modulator of the innate immune system, originally as an intervention to ameliorate graft-versus-host disease in leukemia patients receiving stem cell transplants, or autoimmune diseases. The peptide’s sequence was extracted from OncoImmune’s patent US20130231464A1 the first 30 amino acids are the CD24 region and the remainder belong to the IgG1 Fc domain.
Coronavirus relevance: A clinical stage synthetic fusion protein and CD24 mimetic, that enhances CD24/SIGLEC10 suppression of DAMP-triggered activation of the immune response and associated tissue damage. Repositioned to combat COVID-19 inflammation (currently Phase 3).

Ligand ID: 11421
Names: emvododstat
Comment: Emvododstat (PTC299) is an orally bioavailable inhibitor of dihydroorotate dehydrogenase (DHODH) that was developed by PTC Therapeutics for anti-cancer potential. It inhibits de novo pyrimidine nucleotide (UMP) biosynthesis and exhibits broad activity against leukemia in vitro and in vivo.
Coronavirus relevance: Emvododstat inhibits replication of SARS-CoV-2 in vitro (EC50 2.0-31.6 nM) and other RNA viruses. It blocks production of inflammatory cytokines in infected cell cultures.

2D structure of emvododstat

 

 

 

 

 

 

Ligand ID: 11470
Names: ensovibep (MP0420)
Comment: MP0420 is a DARPin that binds to the SARS-CoV-2 spike glycoprotein, and offers virus neutralising potential. It is being progressed to clinical trial by Molecular Partners and Novartis. DARPins are protein-based therapeutics, with the high selectivity and affinity of antibodies, but are around 10% of the size. They are easier to manufacture than whole antibodies, and may be suitable for subcutaneous administration rather than infusion. Molecular Partners have developed two multi-valent DARPins that are designed to engage multiple sites of the SARS-CoV-2 spike glycoprotein. Novartis and Molecular Partners are working together on both MP0420 and MP0423 for COVID-19.

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Hot Topics: Gene Symbol usage and the need to do better

Posted on January 22, 2021 by guidetopharmacology — Leave a comment

The GtoPdb team need no convincing about the importance of eliminating equivocality in gene and gene product names, as they are used in the pharmacology, chemical biology and drug discovery literature. Crucially, this also applies to their inclusion in curated database bioactivity records such as GtoPdb. We were thus particularly pleased to see “Standardizing gene product nomenclature” that appeared recently in PNAS [1]. This included not only an honourable mention of the Nomenclature Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR) but also the citation of our most recent Concise Guide Introduction [2].

The collaboration between NC-IUPHAR and HGNC for standardising the nomenclature of pharmacological targets goes back well over a decade. This has been (and continues to be) an iterative process whereby NC (after extensive consultation) recommends naming schema for certain target classes that are different to those approved by HGNC. This is typically done on the basis of well established publication usage in the pharmacological community. In many cases these older protein family names predate completion of the human genome. This can be illustrated for the case of the Voltage-gated calcium channels as shown in the GtoPdb family page below.

As we can see in the page for Cav1.1 curation adds a full set of synonyms including CACNA1S and “calcium voltage-gated channel subunit alpha1 S” as approved HGNC Symbol and name, respectively. Below we can see the reciprocal cross-pointing between HGNC and GtoPdb/NC-IUPHAR.

We have commented some time ago on ambiguity issues arising from the necessity of curatorial resolution for authors’ descriptions of key entities to standardized identifiers, including mapping between ligands and target protein names [3]. We consequently hope both papers will contribute to greater use of both HGNC and NC-IUPHAR nomenclature in the pharmacology literature.

Comments by Chris Southan, Fellow of the University of Edinburgh, Owner of TW2Informatics, Chair of NC-IUPHAR Subcommitees for Proteases and Drug Targets and Chemistry (DRUTACS).

[1] Kenji Fujiyoshi, Elspeth A. Bruford, Pawel Mroz, Cynthe L. Sims, Timothy J. O’Leary, Anthony W. I. Lo, Neng Chen, Nimesh R. Patel, Keyur Pravinchandra Patel, Barbara Seliger, Mingyang Song, Federico A. Monzon, Alexis B. Carter, Margaret L. Gulley, Susan M. Mockus, Thuy L. Phung, Harriet Feilotter, Heather E. Williams, and Shuji Ogino (2021) Opinion: Standardizing gene product nomenclature-a call to action, Proc Natl Acad Sci U S A Jan 19;118(3) doi: 10.1073/pnas.2025207118, PMID: 33408252.

[2] Stephen P H Alexander, Eamonn Kelly, Alistair Mathie, John A Peters, Emma L Veale, Jane F Armstrong, Elena Faccenda, Simon D Harding, Adam J Pawson, Joanna L Sharman, Christopher Southan, O Peter Buneman, John A Cidlowski, Arthur Christopoulos, Anthony P Davenport, Doriano Fabbro , Michael Spedding, Jörg Striessnig , Jamie A Davies, CGTP Collaborators (2019) The Concise Guide to Pharmacology 2019/20: Introduction and Other Protein Targets, Br J Pharmacol. Dec; 176 (Suppl 1): S1–S20, PMID: 31710719.

[3] Christopher Southan 1, Joanna L Sharman 1, Elena Faccenda 1, Adam J Pawson 1, Simon D Harding 1, Jamie A Davies 1 (2018) Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Guide to PHARMACOLOGY ACS Omega, Jul 31;3(7):8408-8420, PMID: 30087946.

Posted in Hot Topics

GtoPdb at Pharmacology 2020

Posted on December 16, 2020 by guidetopharmacology — Leave a comment

The BPS Pharmacology 2020 Meeting is being held virtually this year, but this hasn’t diminished Guide to Pharmacology presence.

On Monday 14th, Dr. Simon Harding presented our poster on ‘Expansion for anti-malarial, antibiotics and COVID-19’. Click to view poster.

On Tuesday 15th, Dr. Chris Southan gave on oral presentation on Curating SARS-CoV-2 viral targets for the IUPHAR/BPS Guide to Pharmacology’. The session is currently available ‘on-demand’ at this link. These are available to register attendees for one month.

Chris also presented a poster on ‘SARS-CoV-2/COVID-19 pharmacological roadmap: strategy for curating and updating drug targets in the Guide to Pharmacology Coronavirus Information page’. Click to view poster.

Follow this link to view the GtoPdb Coronavirus Information Page.

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Database Release 2020.5

Posted on November 12, 2020 by guidetopharmacology — 1 Comment

We are pleased to announce the latest release of the Guide to PHARMACOLOGY database, version 2020.5. This is the last planned release for 2020.

The 2020.5 release contains:

  • 1,567 human targets with curated quantitative ligand interactions.
  • 10,659 ligands, 7,884 of which have curated quantitative target interactions.
  • 1,614 approved drugs, 974 with curated quantitative interactions.
  • Clinical use summaries for over 2,800 ligands.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

We have curated some of the entities from the WHO list of COVID-related therapeutics that was released at the end of October: alunacedase alfa, eclitasertib, enpatoran, molnupiravir, nezulcitinib, subasumstat.

Curation Updates

There have been updates to the S1P and LPA receptor families, the bradykinin receptors family, and the S1P turnover enzymes. The P-type ATPases have been expanded and reorganised.

A new family of transporters has been added, SLC66 Lysosomal amino acid transporters, and cyclic GMP-AMP synthase (cGAS) has been added as a new immunopharmacology target.

Website Updates

  • We have started taking step to identify and and fix high-priority accessibility problems
  • Links to AntibioticDB now cover over 280 ligands.

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

 
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Database Release 2020.4

Posted on September 24, 2020 by guidetopharmacology — Leave a comment

The latest release of the Guide to PHARMACOLOGY database, version 2020.4, has now been made.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

GtoPdb curates Coronavirus (CoV) proteins under viral protein targets in our hierarchy. This family contains 15 CoV proteins. Updates in this release to the CoV 3C-like (main) protease include outlinks to CHEMBL (CHEMBL3927) and UniProt (P0C6U8); the addition of 4 further 3D structures (3VB3, 2GX4, 6LZE and 6XHL) and and additional 19 curated ligand interactions.

Curation Updates

We’ve added some new targets proteins along with associated pharmacological ligands. These include the following five, that are all oncology targets:

Also added is C-type lectin receptor CLEC4C, an anti-inflammatory target, and N-acetyltransferase 8 like (ANAT), a target for the treatment of Canavan disease which is a rare aspartoacylase deficiency-mediated neurodegenerative condition.

The list of WHO essential medicines has been expanded with the inclusion of many antibiotics and antivirals.

Overall this release sees updates made to targets across 35 targets families. These are listed below with links to family page in the database:

GPCRs
Adenosine receptors
Bradykinin receptors
Calcium-sensing receptor
Complement peptide receptors
Dopamine receptors
Gonadotrophin-releasing hormone receptors
Hydroxycarboxylic acid receptors
Leukotriene receptors
Melanocortin receptors
Melatonin receptors
Motilin receptor
Neuropeptide S receptor
Neurotensin receptors
Prolactin-releasing peptide receptor
QRFP receptor

Ion-Channels
Glycine receptors
P2X receptors
Voltage-gated potassium channels
Voltage-gated proton channel

Catalytic Receptors
Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase
Transmembrane guanylyl cyclases
Tumour necrosis factor (TNF) receptor family

Enzymes
N-Acylethanolamine turnover
2-Acylglycerol ester turnover
Sphingosine 1-phosphate lyase
Sphingosine 1-phosphate phosphatase
Sphingosine 1-phosphate turnover
Sphingosine kinase

Transporters
Neutral amino acid transporter subfamily
SLC14 family of facilitative urea transporters
SLC28 family
SLC29 family
SLC51 family of steroid-derived molecule transporters
SLC8 family of sodium/calcium exchangers

Other Proteins
R7 family of RGS proteins

Website Updates

  • We updated our website tutorial, which now includes details on the advanced search and ligand activity graphs
  • New download files are available from the immunological process and cell type target associations pages
  • A new GPCR targets download files is available on each of the GPCR list page (example here for Class A)
  • Bug fixes for web services
  • Links to AntibioticDB now cover over 230 ligands.

Guide to Malaria Pharmacology (GtoMPdb)

These are the recent advancements made in the GtoMPdb for this database release:

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Hot Topics: Soluble ligands as drug targets

Posted on September 2, 2020 by guidetopharmacology — Leave a comment

Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters which are primarily targeted by small molecules. However, advances in molecular biology, genomics, and pharmacology have facilitated the development of different therapeutic modalities which in turn have broadened the types of drug targets. In particular, soluble ligands have growing interest as targets and now constitute 10% of novel targets in clinical trials and are currently the third-largest target class of therapeutic agents targeting human protein products, after enzymes and receptors [1].

A new analysis of ligand-targeting [2], illustrates the different classes of ligand-targeting drugs and targets as well as analysing the success of the different technology platforms. This emerging class of drug targets is very dynamic with 291 agents that target 99 unique ligands reaching clinical development from 1992 to 2020. In the last five years, the number of ligand-targeting agents which are FDA-approved has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Therapeutic antibodies are the most common class of both approved and investigative ligand-targeting agents, followed by decoy receptors. Several technology platforms are successfully being developed, enhancing the opportunities of drug development using antibody fragments, single-domain antibodies, aptamers, spiegelmers, engineered protein scaffolds, gene therapy, therapeutic vaccines and oligonucleotides. There is an increase in the number of agents that target more than one ligand, as well as the number of unique combinations of ligands. Advances in engineering technology and the ability to effectively and safely target more than one ligand has combined with increased knowledge of disease pathways to effectively utilize bispecific antibodies and decoy receptors, amongst others, to selectively disrupt multiple biological pathways by blocking two (or more) related or unrelated ligands. Cytokines and growth factors are the predominant types of targeted ligands (70%), which is consistent with the three major disease groups being treated by both approved and investigational agents: inflammation and autoimmune diseases, cancer, and ophthalmological diseases.

Several factors contribute to the increasing importance of soluble ligands as drug targets, including the growing understanding of the role of the immune system in many diseases in conjunction with the tractability of cytokines as therapeutic agents, and the relative accessibility of ligands in comparison to their receptors to therapeutic agents. Given the increasing body of evidence that inflammation is involved in many diseases beyond typical inflammation disorders and the position of ligand-targeting drugs at the forefront of anti-inflammatory therapies, there will be continued interest in this class of agents. Furthermore, there is vast territory to explore in the ligand target landscape, as there are almost 600 endogenous human peptides according to IUPHAR/BPS Guide to PHARMACOLOGY (https://www.guidetopharmacology.org) with approximately 150 of these identified as having specifically curated immunopharmacological data associated with them (IUPHAR Guide to IMMUNOPHARMACOLOGY: https://www.guidetoimmunopharmacology.org/immuno/).

In conclusion, ligands as a type of drug target now merit consideration as a distinct and expanding group of targets for a range of therapeutic modalities that can exert their effects through single targets or selected combinations.

Comments by Misty Attwood and Helgi Schiöth, University of Uppsala, Uppsala, Sweden. Helgi Schiöth is Chair for NC-IUPHAR Subcommitees for Melanocortin receptors and Prolactin-releasing peptide receptor. Twitter: @FunctPharm

  1. Attwood, M. M., Rask- Andersen, M. & Schiöth, H. B. Orphan drugs and their impact on pharmaceutical development. Trends Pharmacol. Sci. 39, 525–535 (2018). [PMID: 29779531]
  2. Attwood, M.M., Jonsson, J., Rask-Andersen, M & Schiöth, H. B. Soluble ligands as drug targets. Nature Reviews Drug Discovery. Online ahead of print (2020 Sep 2.). [PMID: 32873970]
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GtoPdb pre-release ligands (2020.4)

Posted on August 3, 2020 by guidetopharmacology — Leave a comment

These are some of the ligands under curation (pre-release) in the Guide to Pharmacology. We expect them to be available on the website at the next database release (2020.4).

Ligand ID: 11132

Name: otilimab

Comment: Otilimab (MOR103, GSK3196165) is a clinical stage fully human IgG1λ antibody that targets the granulocyte-macrophage colony-stimulating factor (GM-CSF; CSF2). It is being investigated as a therapeutic for inflammatory diseases. MOR103 was developed using MorphoSys’ HuCAL® technology, and has been fully out-licensed otilimab to GSK. MOR103 is claimed as MOR-04357 in patent WO2006122797A2 (by BLAST peptide sequence matching).

Ligand ID: 11139

Name: favipiravir

11139

Comment: Favipiravir (T-705) is an orally delivered, guanine (purine) analogue antiviral drug (cf. remdesivir which is administered i.v.). It targets viral RNA-dependent RNA polymerase (RdRP) of RNA viruses and since the catalytic domain of RdRP is well conserved across species, has a broad-spectrum of activity; although Furuta et al. (2002) reported that actvity was weak against non-influenza virus RNA viruses [4]. Favipiravir was originally identified through a chemical library screen against influenza virus RdRP [3]. Chemically, it is a prodrug. In human cells it undergoes phosphoribosylation and phosphorylation to its active form, favipiravir-ribofuranosyl-5′-triphosphate (F-RTP). F-RTP is bound by the RdRP, but it blocks enzyme activity and so terminates chain elongation [5-6].

IUPAC Name: 5-fluoro-2-oxo-1H-pyrazine-3-carboxamide

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Hot Topics: TMEM163 regulates ATP-gated P2X receptor and behaviour

Posted on July 8, 2020 by guidetopharmacology — Leave a comment

It is now clear that ligand-gated ion channels (LGICs) are not “stand alone” functional units, but form complexes with other components, including scaffolding proteins, regulatory proteins and enzymes. Besides their important physiological roles, these modulating proteins are also potential targets for drug discovery. P2X receptors are LGICs for which ATP is the endogenous agonist. Seven P2X subunits have been identified and they form trimers to produce at least twelve different receptor subtypes. Here, the authors combined a genome-wide open reading frame (ORF) collection with high-throughput functional screening, to search for P2X receptor modulators.

They first created a HEK-293 cell line that stably expressed human P2X2 plus P2X3 receptors, then one-by-one, co-expressed each of 17,284 non-redundant ORFs, which represents 90% of the known human protein-coding genes. They then compared the rise in intracellular [Ca2+] induced by the P2X3 agonist α,β-meATP, using a composite score of four measurements; 1) baseline, 2) peak and 3) steady-state [Ca2+], along with 4) time-course of the decay of the peak. The highest scoring ORFs were then co-expressed with P2X3 receptors in Xenopus laevis oocytes and their effects on ATP-induced ion currents determined. This process led to TMEM163 being identified as a modulator of P2X3 receptors.

TMEM163 comprises 289 amino acids, with a molecular weight of 31 kDa and predicted secondary structure of six transmembrane-spanning domains with intracellular NH2– and COOH-termini. When expressed on its own, TMEM163 had no ATP-dependent activity and when co-expressed, had no effect on the activity of AMPA, kainate, muscarinic or P2X2 receptors, nor on endogenous P2Y receptors in HEK-293 cells. It did, however, potentiate ATP-evoked currents mediated by P2X1 and P2X4 receptors and conversely, inhibited currents carried by P2X7 receptors. Thus TMEM163 appears to selectively modulate P2X receptor activity, but in a subtype-specific manner.

More detailed analysis of its actions showed that TMEM163 potentiated P2X3 receptors by shifting the ATP concentration-response curve (CRC) to the left, with a five-fold decrease in the EC50 and slowing the time-course of current decay. Surprisingly, it also substantially reduced the surface expression of P2X3 receptors. In contrast, the inhibitory effects on P2X7 receptors were associated with a decrease in both the potency of ATP and surface expression of the receptor.

Next, the expression and effects of native TM163 was investigated in mice. In situ hybridisation and an anti-TM163 antibody showed TMEM163 to be present in primary cultures of mouse cerebellar neurones. Infection with a TMEM163 shRNA reduced protein expression by almost half and the peak amplitude of ATP-induced ion currents by a third. The effect on P2X3 receptor protein levels was not reported, however. To study its role in vivo, TMEM163 was knocked-out using CRISPR/Cas9 and pain-associated behaviour induced by ATP injection into the hind-paw studied. There was no difference in paw lifting between wild-type and knock-out mice, but freezing behaviour was reduced by about 50%. Notably, and in contrast to the data obtained using recombinant TMEM163, the total amount of P2X3 protein in dorsal root ganglion was unchanged. The ATP CRC was, however, shifted about five-fold to the right by TMEM163 knock-out, consistent with the leftwards shift seen using the recombinant proteins.

By showing that that TMEM163 selectively modulates P2X receptor activity and in a subtype-specific manner, this study greatly improves our understanding of how native P2X receptors function. As such, TMEM163 is potentially a new target for drug discovery.

Comments by Charles Kennedy, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. Chair for NC-IUPHAR Subcommitee for P2X receptors.

  1. Salm EJ, Dunn PJ, Shan L, Yamasaki M, Malewicz NM, Miyazaki T, Park J, Sumioka A, Hamer RRL, He WW, Morimoto-Tomita M, LaMotte RH, Tomita S. (2020). TMEM163 regulates ATP-gated P2X receptor and behaviour. Cell Rep, 31: 107704. PMID: 32492420.

 

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Accessing WHO Essential Medicines in GtoPdb

Posted on June 26, 2020 by guidetopharmacology — Leave a comment

The Guide to Pharmacology (GtoPdb) currently contains data on over 10,000 different ligands which are categorised into an number of different groups or classifications. The ligand list page (https://www.guidetopharmacology.org/GRAC/LigandListForward?type=WHO-essential&database=all) provides a directory of all the ligands described in the database, divided into subsets according to chemical category.

We have recently added a WHO Essential Medicine subset, which contains ligands in GtoPdb that are also in the latest WHO Model List of Essential Medicines (21st list, 2019) (https://www.who.int/medicines/publications/essentialmedicines/en/). This totals 224 ligands in our 2020.3 release.

Selecting the WHO tab from the ligand list page shows this subset (Figure 1). Users can also download this set of ligands (as csv file) by clicking on the link in the top-right.

Accessing WHO tagged GtoPdb compound in PubChem

GtoPdb regularly uploads its set of compounds to PubChem, which provides all GtoPdb ligands with PubChem Substance Identifiers (SIDs), which are in turn mapped (by PubChem) to PubChem Compound Identifiers (CIDs). As part of our PubChem upload process we have developed our curatorial tagging within the depositor comment sections in the substance records (SIDs). This means users are able to make domain-specific queries, to be executed from both the PubChem Substance (SID) and PubChem Compound (CID) interfaces, by using an advanced search of ‘comments’ fields.

We have now added a WHO tag to the comments fields in our PubChem upload (see example for cholorquine, Figure 2). chloroquine2

Figure 2. Depositor comment for Chloroquine (PubChem Substance ID 178102177) showing GtoPdb curatorial tagging to mark substance as included in WHO Essential Medicines List. https://pubchem.ncbi.nlm.nih.gov/substance/178102177#section=Depositor-Comments

Therefore it is now possible, through the query below to easily access the WHO Essential Medicines in GtoPdb through PubChem.

https://www.ncbi.nlm.nih.gov/pcsubstance?term=(%22iuphar%2Fbps%20guide%20to%20pharmacology%22%5BSourceName%5D)%20AND%20%22gtopdb%20who%22%5BComment%5D

pubchem_gtopdb_who


Figure 3. Search result in PubChem for IUPHAR/BPS Guide to PHARMACOLOGY substances that include ‘gtopdb_who’ in the comments. https://www.ncbi.nlm.nih.gov/pcsubstance/?term=(%22iuphar%2Fbps+guide+to+pharmacology%22%5BSourceName%5D)+AND+%22gtopdb+who%22%5BComment%5D

 

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Database Release 2020.3

Posted on June 19, 2020 by guidetopharmacology — Leave a comment

The latest release of the Guide to PHARMACOLOGY database, version 2020.3, has now been made. A large focus of our curation over the last couple of month since our 2020.2 release We are pleased to have been able to make an expeditious database release (version 2020.2), following on from our last update in March 2020 in order to make public new curation specifically related to SARS-CoV-2.

Coronavirus

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

Recently published in BJP is our review that “sets out to identify opportunities for drug discovery in the treatment of COVID‐19 and in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic“:

Alexander SPH, Armstrong J, Davenport AP, Davies JA, Faccenda E, Harding SD, Levi-Schaffer F, Maguire JJ, Pawson AJ, Southan C, Spedding MJ. (2020). A rational roadmap for SARS‐CoV‐2/COVID‐19 pharmacotherapeutic research and development. IUPHAR Review 29 Br J Pharmacol. doi: 10.1111/bph.15094. [PMID:32358833]

Content Updates

Main target families with updated in this release:

GPCRs

Ion Channels

NHRs

Enzymes, Catalytic Receptors

New drug target

Acyl-CoA synthetase short chain family member 2 (ACSS2) is an emerging oncology drug target that plays a role in epithelial-mesenchymal transition (EMT) and cancer cell metastasis. Two ACSS2 inhibitor probe compounds have been curated.

AntibioticDB

As part of a collaboration with AntibioticDB (https://www.antibioticdb.com/), we have now begun to identify and tag sets of antibiotic ligands in GtoPdb. Where we have identified mappings between these and compounds in the AntibioticDB repository, we’ve put in place direct links. The newly curated set includes approved and investigational antibiotics and pre-clinical leads, as well as compounds whose development has been discontinued.

teixobactin

Teixobactin ligand summary page (https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10972). At the bottom, a new specialist database link now existing to the mapped entry in AntibioticDB.

Website Updates

Ligand Summary Pages

The layout of the ligand summary pages has been changed to hopefully provide more of the key information on a ligand at the top of these pages. In the example below we show how this looks for chloroquine.

chloroquine

The main information box now contains:

  • Synonyms
  • Icons to indicate key ligand classifications
  • Drug approval indication
  • GtoPdb curator comments
  • Link to ligand activity graphs

In addition, the 2D ligand structure is display beside this information in a expandable/retractable section where users can also view physico-chemical properties and SMILES/InChI/InChI Keys.

Previously the top part of the ligand summary pages contained too much white space, repetitions of the ligand name and emphasised the ligand ID, physico-chemical properties and to some extent buried comments, SMILES/InChI keys and useful links (such as to the ligand activity graphs).

The reorganisation of the page now emphasises key information. GtoPdb curator comments in particular contain a valuable description of the ligand and provide explanations as to why they have been curated in GtoPdb.

WHO essential medicines

Any ligands included in the World Health Organization (WHO) Model List of Essential Medicines (21st list, 2019) are now tagged in GtoPdb. This means users can easily view these ligands on our ligand list page:

https://www.guidetopharmacology.org/GRAC/LigandListForward?type=WHO-essential&database=all

It is also possible, as it is for all ligand lists, to download this set from this page by clicking the download link in the top-right of the table (see below).

who_list

Other Updates

ChEMBL 27

Both the ligand activity graphs and pharmacology search tools have now been updated to access the latest ChEMBL release (ChEMBL 27).

Links to DrugCentral 2020

We have added links to the DrugCentral 2020 Online Drug Compendium. DrugCentral provides information on active ingredients chemical entities, pharmaceutical products, drug mode of action, indications, pharmacologic action. It monitors FDA, EMA, and PMDA for new drug approval on regular basis to ensure currency of the resource. Limited information on discontinued and drugs approved outside US is also available however regulatory approval information can’t be verified. The database is developed and maintained by Oleg Ursu and Tudor Oprea and the web application is developed by Jayme Holmes.

We have so far mapped 1433 ligands in GtoPdb to entries in DrugCentral.

 

 

 

 

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Hot Topics: A trio of GPCR peptide publications

Posted on May 17, 2020 by guidetopharmacology — Leave a comment

This post covers three recent publications with a common theme and whose authors are collaborators with GtoPdb, thus making them as a trio particularly suitable for combined review.  These are; Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors [1], Novel approaches leading towards peptide GPCR de-orphanisation [2] , and  Advances in therapeutic peptides targeting G protein-coupled receptors [3].  As expected, these are all clearly written, contain  valuable detail  and each includes its own introduction.  Therefore this piece does not need to go over these works per se but simply point out their coverage, domain of application, along with brief explanations of entity linking and/or external look-up options.

For context,  it should be pointed out that historical success in de-orphanising GPCRs (i.e.  reproducibly pairing them with physiologically-relevant endogenous ligands) has been difficult and slow. This remains so,  despite decades of  intense effort from not only all major pharmaceutical companies but also academic groups utilising various flavours of  de-orphanistaion screening approaches and technologies. This was pursued in parallel with cloning (and patenting) the complete repertoire of human GPCRs as they slowly came into view.  Initially done via mining millions of expressed sequence tag (EST) transcripts in the mid 90’s, this later shifted focus to genomic DNA  surfacing between appropriately 1998 and 2000. The modest progress even after the completion of the draft human genome can be discerned from the table below compiled in 2000 [4].

Capture

Progress ~ 2000- 2018 is outlined both in  Concise Guide 2019/20 : G Protein-Coupled Receptors (PMID: 31710717)  [5] and in the Guide to Pharmacology latest parings list .

As the first of this trio of papers, Foster et al.  [1] have significantly advanced the de-orphanisation field in 2019 by integrating computational and experimental approaches for peptide-GPCR pairings.  They began with comparative sequence and structural analyses to gain biological insights into the  human peptide-receptor signalling landscape. They were then able to leverage these features to mine candidate peptide ligands from the entire human genome,  arranged for these to be synthesised and then tested for activity in a broad range of pairing assays that included known ligands as positive controls.  The impressive scope of  results is indicated  in their Fig 7 (below).

Capture

In summary, the 53 peptides with validated receptor-dependent responses first reported in this paper,  has  expanded the known human peptidergic signaling network from 348 to 407 interactions.  It is also important to note that they were unable to reproduce no less than six reported parings in the literature from 2004 to 2016 (i.e. those de-orphanisations could not be verified).

In collaboration with the Copenhagen crew, this paper was curated by the GtoPdb team according to their target mapping stringency and potency thresholds.  Consequently, 11 new peptides have been  annotated with the quantitative ligand binding data reported for the newly de-orphanised receptors.  These are shown below with their PubChem Substance Links  (SIDs) for which GtoPdb (so far) has becomes the only source of these compound structures (CIDs) from over 730 submitters.

CaptureIn PubChem these can be accessed by scrolling down to “Related information”  on the lower right hand facet of PMID: 31675498  and clicking on “PubChem Substance”.  Each entry has a pointer back to GtoPdb from the SID and the nomenclature of  the peptides matches that used in the paper.  However, users wanting to select these entries from within GtoPdb can go to Ligand Search Tools > Search for data by literature reference >   Enter PubMed Id: 31675498 >  Select field to search: PubMed ID.   This brings back 16 entries since it includes the 11 ligands above plus the five receptors for which binding data was curated  (n.b. these instructions apply to the old PubMed interface, so some of this may change for the new interface).  While the version of the article  in Cell journal  itself has no entity outlinks (except for references)  the PubMed Central version has automatically linked the PDB IDs.  All the GPCR protein/gene names should retrieve in GtoPdb or of course GPCRdb

The second article in the trio is a review  by Hauser et al [2].  This  covers some of the same ground as above but includes an assessment of contemporary methodologies of de‐orphanisation.  The informative Figure 1, summarising extensive data mining, is shown below.

Capture

In addition to indicating the ligand status of the GPCRs the circles extend to clinical relevance, disease therapeutic potential,  publication density and tool compounds from ChEMBL.  Note that  while ChEMBL links to compounds with a wide range of potentcies GtoPdb has a more stringent  annotation of smaller number of probe candidates including very recent publications (e.g. these 11 ligands above are not in ChEMBL26).

One of the advantages of publishing in BJP is the provision of author-specified out-links to GtoPdb ligands and targets (see PMID 30087946).  These have been duly added to the  PDF for all GPCRs mentioned in the text as well as any ligands that were already in GtoPdb before this review.  Examples for five links are shown below.

Capture

Clicking on “GPR15” above thus takes us the full annotation for that receptor, including the agonist ligand records shown below.

Capture

Thus GPR15L (71-81)  corresponds to SID 404859015.  The format of Table 1 unfortunately precluded the addition of the live-links for the new ligands.

The last of this trio is an in-depth review by Davenport et. al. [3] that encompasses translation aspects of peptides that modulate GPCRs into clinically effective drugs. This may even eventually extent to analogues of the peptides from the first two papers perhaps even related to new de-orphanisations.  As detailed in this review therapeutic peptides have recently been  undergoing a development technology renaissance via half- life extension, stapling and resistance to proteolysis. These measures  improve pharmacokinetics and oral bioavailability that have hitherto been much less favourable for peptidic structures in comparison to conventional small-molecule drug candidates.  An overview of these peptide approvals and advanced candidates is taken from their Figure 1.

Capture

This comprehensive review goes on to describe in detail 26 synthetic peptides  approved for clinical use  (20 agonists and 6 competitive antagonists) targeting eight class A receptor families.  It also includes a useful  structural perspectives not only on peptide binding sites but also addresses the frequently overlooked aspects associated with unnatural amino acids and chemical modifications.

It seems somewhat anachronistic  that the  Nat Rev Drug Discov  PDFs are entity link-free zones (although this FAIR-gap  has been pointed out to them).  Notwithstanding, the GPCR names should retrieve cleanly from GtoPdb and GPCRdb.  Most of the peptide names in the review should also retrieve their ligand entries from GtoPdb but these will eventually be cross-checked both for the resolution of equivocalities and addition of new development candidates with referenced binding data.

Constituting a well-referenced overview of  the field, these three papers also represent  “good news” for peptides and their analogues.  Notwithstanding,  this slide set outlines some of the challenges for curating peptides and searching them in databases.

**********************************

Comments by Chris Southan, Fellow of the University Edinburgh,  Owner of TW2Informatics ,  Chair of NC-IUPHAR Subcommitees for Proteases and  Drug Targets and Chemistry (DRUTACS),  ORCID 0000-0001-9580-0446.  As declaration of interest (but not conflict!)  Chris was pleased to be a co-supervisor for Alex Hauser’s PhD work on Computational Receptor Biology

[1] Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors.  Foster SR, Hauser AS, Vedel L, Strachan RT, Huang XP, Gavin AC, Shah SD, Nayak AP, Haugaard-Kedström LM, Penn RB, Roth BL, Bräuner-Osborne H, Gloriam DE. Cell. 2019 Oct 31;179(4):895-908.e21. doi: 10.1016/j.cell.2019.10.010.  PMID: 31675498.

[2]  Novel approaches leading towards peptide GPCR de-orphanisation.  Hauser AS, Gloriam DE, Bräuner-Osborne H, Foster SR. Br J Pharmacol. 2020 Mar;177(5):961-968. doi: 10.1111/bph.14950. Epub 2020 Feb 3. PMID: 31863461.

[3] Advances in therapeutic peptides targeting G protein-coupled receptors.  Anthony P. Davenport AP, Scully CCG , de Graaf C, Brown, AJH,  Maguire JJ.  Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-020-0062-z.

[4]  The impact of genomics on drug discovery. Beeley LJ, Duckworth DM, Southan C.  Prog Med Chem. 2000;37:1-43. PMID: 10845246. 

[5]  The Concise Guide to PHARMACOLOGY 2019/20 : G Protein-Coupled Receptors. Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. Br J Pharmacol. 2019 Dec;176 Suppl 1:S21-S141. doi: 10.1111/bph.14748.  PMID: 31710717.

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GtoPdb pre-release ligands (2020.3)

Posted on May 4, 2020 by guidetopharmacology — Leave a comment

These are some of the ligands under curation (pre-release) in the Guide to Pharmacology. We expect them to be available on the website at the next database release (2020.3).

Ligand ID: 10891

Name: aviptadil

10891

Comment: Aviptadil is a vasoactive intestinal peptide analogue, VPAC1 receptor agonist.
The HELM annotation for aviptadil is PEPTIDE1{H.S.D.A.V.F.T.D.N.Y.T.R.L.R.K.Q.M.A.V.K.K.Y.L.N.S.I.L.N}$$$$.

Ligand ID: 10745

Name: MDL-28170

IUPAC: benzyl N-[(2S)-3-methyl-1-oxo-1-[[(2S)-1-oxo-3-phenylpropan-2-yl]amino]butan-2-yl]carbamate

Comment: PRD_002214 is a peptide-like inhibitor of the main protease (MPRO) of SARS-CoV-2. The structure was obtained from the RCSB Protein Data Bank entry 6LU7 which shows the ligand in complex with the protease. The article describing the work has not yet been published (March 12, 2020), but the inhibitor (also referred to as N3) has been deployed in other MPRO crystallisation studies (Yang et al. (2005)).

Ligand ID: 10752

Name: leronlimab

Comment: Leronlimab (PRO140) is a humanized anti-CCR5 (C-C motif chemokine receptor 5) monoclonal antibody [5-6]. It was originally developed by CytoDyn as a novel strategy to manage CCR5-tropic HIV infection.COVID-19: Leronlimab has been administered to a number of patients with severe COVID-19, to determine its potential to reduce cytokine storm caused by this disease.

Ligand ID: 11026

Name: meplazumab

Comment: Meplazumab is a humanized IgG2 monoclonal antibody that targets CD147 (basigin). It is being developed by Jiangsu Pacific Meinuoke Bio Pharmaceutical.

COVID-19
SARS-CoV-2 may utilise CD147 as an additional entry receptor to infect host cells [2]. Meplazumab can block this interaction between CD147 and SARS-CoV-2 spike protein.

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Database Release 2020.2

Posted on April 20, 2020 by guidetopharmacology — Leave a comment

We are pleased to have been able to make an expeditious database release (version 2020.2), following on from our last update in March 2020 in order to make public new curation specifically related to SARS-CoV-2.

Content Updates

  • GtoPdb now includes a new SARS-Cov-2 protein family which includes 13 members and is included under ‘anti-infective targets’ in our hierarchy
  • The new targets in the SARS-CoV-2 protein family have been mapped to UniProt accessions were possible. Because so little is yet understood about SARS-CoV-2 at the molecular level, much of what is curated for these proteins has been predicted and/or extrapolated from what is known about SARS-CoV and MERS-CoV. We will of course update the pages as and when new data are published.
  • Several new compounds, relevant to SARS-CoV-2 have now been added, including PRD_002214 and compound 13b (virus main protease inhibitors), otamixaban and I-432 (potential TMPRSS2 inhibitors), and β-D-N4-hydroxycytidine (a broad spectrum antiviral compound).

The Guide to Pharmacology coronavirus information page continues to be updated on a regular basis to capture the latest pharmacological strategies under investigation to mitigate against COVID-19.

 

 

Posted in Database updates, Technical

GtoPdb pre-release ligands (2020.2)

Posted on March 13, 2020 by guidetopharmacology — Leave a comment

These are some of the ligands under curation (pre-release) in the Guide to Pharmacology. We expect them to be available on the website at the next database release (2020.2 – no earlier than April 2020).

  •  Ligand ID: 10716
    • Name: PRD_002214
    • 10716
    • IUPAC: benzyl (2Z,4S)-4-[(2S)-4-methyl-2-[(2S)-3-methyl-2-[(2S)-2-[(5-methyl-1,2-oxazol-3-yl)formamido]propanamido]butanamido]pentanamido]-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate
    • RCSB PDB: PRD_002214
    • Comment: PRD_002214 is a peptide-like inhibitor of the main protease (MPRO) of SARS-CoV-2. The structure was obtained from the RCSB Protein Data Bank entry 6LU7 which shows the ligand in complex with the protease. The article describing the work has not yet been published (March 12, 2020), but the inhibitor (also referred to as N3) has been deployed in other MPRO crystallisation studies (Yang et al. (2005))
  • Ligand ID: 10720
    • Name: compound 13b
    • Click here for structure editor
    • IUPAC: Tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)-butan-2-yl)ami-no)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate
    • Comment: Compound 13b is an inhibitor of SARS-CoV-2 main protease (Mpro) [3]. It is a derivative of the prevoiusly reported α-ketoamide inhibitor compound 11r [PMID: 32045235][1]. Compound 13b has an enhanced plasma half-life compared to 11r, plus it exhibits substantial lung tropism and has shown suitability for inhalation-mediated administration.
  • Ligand ID: 10732
      • Name: otamixaban
      • Click here for structure editor
      • IUPAC: methyl (2R,3R)-2-[(3-carbamimidoylphenyl)methyl]-3-[[4-(1-oxidopyridin-1-ium-4-yl)benzoyl]amino]butanoate
      • Comment: Otamixaban (FXV673) is an anticoagulant that was originally reported by Aventis Pharmaceuticals (Sanofi). It is a potent and selective direct inhibitor of coagulation factor Xa that is delivered intravenously. The INN record stipulates the (2R,3R) configuration. Virtual docking studies suggest that otamixaban may bind to the serine protease TMPRSS2, which is linked to host cell entry by a number of viruses, in particular influenza viruses and respiratory viruses such as SARS-CoV-2. Inhibition of TMPRSS2 is being examined for antiviral activity. The TMPRSS2 inhibitory potential and/or antiviral activity of otamixaban have not yet been determined.
  • Ligand ID: 10733
    • Name: I-432
    • Click here for structure editor
    • IUPAC: 3-[(2R)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[3-(4,6-dichlorocyclohexa-1,5-dien-1-yl)benzenesulfonamido]-3-oxopropyl]benzene-1-carboximidamide
    • Comment: I-432 is an inhibitor of the serine protease TMPRSS2. TMPRSS2, present in human airway cells, is involved in processes that support infection by a number of viruses, thus inhibitors of this protease are being investigated for anti-viral potential
  • Ligand ID: 10735
    • Name: β-D-N4-hydroxycytidine
    • Click here for structure editor
    • IUPAC: 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-(hydroxyamino)pyrimidin-2-one
    • Comment: Preliminary evidence from a BioRxiv preprint indicate that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
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Posted in Database updates

Database Release 2020.1

Posted on March 12, 2020 by guidetopharmacology — Leave a comment

We are pleased to announce our first database release of 2020 – version 2020.1.

Coronavirus (Covid-19)

We have added a new coronavirus page to the Guide to Pharmacology which aims to consolidate key pharmacological information and resources related to coronavirus. We have gathered information from various sources, with an aim to cover as many of the pharmacological strategies being considered as we could find. Links are provided to the key ligands and target pages in GtoPdb (where data is available). The page also provides other useful links and resource. We will aim to keep this page updated in this fast changing situation.

Tools

GtoPdb contains a couple of useful tools for searching and visualising pharamcology data – that combine data from ChEMBL with GtoPdb data. In this release we’ve update our site to make accessing the visualisation charts easier

Ligand Activity Charts

This tool provides charts with box plots summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Separate charts are created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

Previously, access to the charts was only found on a ligand’s summary page, under the biological activity tab. We’ve now moved that link so it appears more prominently on these pages.ligSumLink

We have also added a new icon on the ligand list pages which indicated whether there are activity charts available for the ligand. Click the icon takes the users straight to the charts.

iconImage

New ‘bar-chart’ icon added to ligand list to indicate availability of activity charts

Publications

We have published a review of the Guide to Immunopharmacology in Immunology at the start of the year. The review provides a deeper context for how the resource can support research into the development of drugs targeted at modulating immune, inflammatory or infectious components of disease.

Harding, S. D., Faccenda, E., Southan, C., Pawson, A. J., Maffia, P., Alexander, S., Davenport, A. P., Fabbro, D., Levi-Schaffer, F., Spedding, M., & Davies, J. A. (2020). The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacology. Immunology, 10.1111/imm.13175. Advance online publication. https://doi.org/10.1111/imm.13175

Content Updates

GPCRs:

Ion Channels:

NHRs:

Enzymes and Other Protein Targets:

Guide to Malaria Pharmacology Updates:

  • 3 P. falciparum (3D7) targets have been added to the Antimalarial targets family: PfCLK3, PfPMV and PfNCR1
  • The Antimalarial ligands family now contains a total of 80 ligands tagged as antimalarial in the database

Other Updates

Updated display of ligand clinical trial data

The ligand summary pages have been updated to improve the display of clinical trials information. Key clinical trials involving the ligand are now displayed in a separate table, under the clinical data tab. The table includes link out the clinical trial plus trial title, type, source, curator comments and references.

clinical_trial_snapshot

Approved drug with primary targets download

A new download file of all approved drugs and their primary targets has been added to the download page.

New out-links

  • Marine pharmacology – Marine Pharmacology (Midwestern University): a website aimed at those with an interest in the preclinical and clinical pharmacology of marine compounds and the pharmaceutical potential of the enormous biodiversity of organisms present in the world’s oceans
  • Pharos – Pharos is the user interface to the Knowledge Management Center (KMC) for the Illuminating the Druggable Genome (IDG) program
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Posted in Database updates, Technical

Hot Topics: Virtual screening on the crystal structure of the G protein-coupled melatonin MT1 receptor reveals several new chemical scaffolds with biological activity

Posted on March 9, 2020 by guidetopharmacology — Leave a comment

Melatonin targets two high-affinity receptors, MT1 and MT2, that belong to the G protein-coupled receptor (GPCR) superfamily (1,2). Drugs acting on melatonin receptors are subscribed for circadian disorders (jet lag, shift work, etc.), insomnia and major depression (3). All marketed drugs are non-selective agonists targeting both receptor types so far. Despite large chemical synthesis campaigns over the last 20 years, the pharmacology of melatonin receptors remains poorly explored with few inverse agonistic and signaling pathway-biased compounds and few  selective compounds, in particular for the MT1 type (2,4). This lack of pharmacological tools goes along with a rather poor diversity in terms of chemical scaffolds currently available (5). Put into this context, a virtual screening looked like a very promising approach to increase the diversity of chemical scaffolds for melatonin receptors, especially now that the crystal structure of the MT1 receptor has been solved (6). The outcome of the virtual screening study performed by Stein et al. (7) met these high expectations. Overall, 15 new chemical scaffolds were identified from the primary docking of over 150 million virtual molecules (7). Some of the primary hits had pEC50 values around 1nM, which is remarkable. In terms of functional properties, primary hits and derivatives showed agonistic and inverse agonistic properties with or without selectivity for MT1 and MT2. Two MT1 selective inverse agonists were further validated in vivo regarding their effects on circadian rhythm parameters in mice under free-running conditions, as well as using an experimental re-entrainment protocol corresponding to an ‘east-bound’ jet lag paradigm.

This study is not only of great value for the melatonin receptor field but will also encourage virtual screening approaches on other GPCRs for which high-resolution structures are available. Compared to other GPCR structures, the MT1 template structure has several limitations as it was in the inactive form despite the presence of the 2‐phenylmelatonin agonist, and it was heavily modified with 9 point mutations and several truncations to facilitate expression and stability (7,8). However, a favorable feature of MT1 for virtual docking might be its ligand binding pocket which is rather small and hydrophobic with only two key residues important for high-affinity binding. This limits the number of poses to be screened by virtual docking. Moreover, although the screening was designed to identify MT1 selective compounds, positive hits included also MT2 selective and non-selective compounds suggesting that virtual screening is currently unable to predict type selective compounds. This might also depend on the quality of the receptor structure and the degree of divergence between receptor types.

In conclusion, this article is a nice example of successful virtual screening on GPCRs, one of the desired benefits of crystal structures, that will accelerate the drug development process towards compounds with improved efficacy and target-selectivity.

This study investigated two MT1-selective inverse agonists, UCSF7447 and UCSF3384, and a selective MT2 agonist, UCSF4226, for their affinities.

Comments by Ralf Jockers, Institut Cochin, CNRS, INSERM, Université de Paris, Paris, France, Chair for NC-IUPHAR Subcommitee for Melatonin receptors.

  1. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010;62(3):343-380.
  2. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on Melatonin Receptors. IUPHAR Review. Br J Pharmacol. 2016;173(18):2702-2725
  3. Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-383.
  4. Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol. 2017;175:3263–3280.
  5. Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA. MT1 and MT2 Melatonin Receptors: Ligands, Models, Oligomers, and Therapeutic Potential. J Med Chem. 2014;57(8):3161-3185.
  6. Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, Gati C, Batyuk A, Slocum ST, Ishchenko A, Brehm W, White TA, Michaelian N, Madsen C, Zhu L, Grant TD, Grandner JM, Shiriaeva A, Olsen RHJ, Tribo AR, Yous S, Stevens RC, Weierstall U, Katritch V, Roth BL, Liu W, Cherezov V. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature. 2019;569(7755):284-288.
  7. Stein RM, Kang HJ, McCorvy JD, Glatfelter GC, Jones AJ, Che T, Slocum S, Huang XP, Savych O, Moroz YS, Stauch B, Johansson LC, Cherezov V, Kenakin T, Irwin JJ, Shoichet BK, Roth BL, Dubocovich ML. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature. 2020. [PMID: 32040955]
  8. Cecon E, Liu L, Jockers R. Melatonin receptor structures shed new light on melatonin research. J Pineal Res. 2019:e12606.
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Hot Topics: Cardiac Ca2+ Channel Regulation in the Fight-or-Flight Response: the monomeric small G-protein as another piece in the puzzle

Posted on February 12, 2020 by guidetopharmacology — Leave a comment

Thirty eight years after the discovery that injection of the catalytic subunits of cyclic AMP-dependent protein kinase A (PKA) into isolated pig ventricular cardiac myocytes (1) increases the amplitude of L-type Ca2+ current (today known to be formed by Cav1.2 channels, (2)), we are now getting close to understand the responsible molecular mechanism. Initial research that has focused on direct regulatory mechanisms, such as the activation by the α-subunit of the stimulatory heterotrimeric G-protein Gs (3), and direct phosphorylation of the pore-forming α1- or accessory β2-subunit of the Cav1.2 channel has not provided a conclusive answer. β-adrenergic modulation was not (α1 Ser-1928, (4)) or only partially (α1 Ser-1700/Thr-1704, (5)) prevented in mutant mice lacking predicted phosphorylation sites in α1 or β2 subunits (6). This was further supported by an elegant transgenic approach showing that expression of channel complexes with all PKA consensus sites mutated to alanine in the Cav1.2 α1 and the β2 subunits (7) has no effects on β-adrenergic modulation.

Assuming that other proteins may be involved in this regulatory pathway, Liu et al. (7) used a biotinylation-based proteomic proximity assay to identify proteins in the Cav1.2 neighborhood regulated by isoproterenol treatment in cardiomyocytes. This led to the discovery of the small Ras-like G protein Rad as a potential candidate. It belongs to the family of the Rad, Rem, Rem2 and Gem/Kir (RGK) Ras-like GTP-binding proteins, which were shown earlier to inhibit high-voltage-activated Ca2+ channels by binding to their β-subunits. Indeed, Rad appears to be the long-sought missing piece in the puzzle: in HEK293T Rad-mediated inhibition of cardiac Cav1.2 channels was relieved by PKA phosphorylation. Modulation was prevented either by the simultaneous mutation of the known cardiac PKA phosphorylation sites of Rad to alanine or by inhibiting the interaction of Rad with the β-subunit.

This mechanism may be universal and may also explain the PKA modulation of other types of β-subunit associated high-voltage activated Ca2+ channels in Rad expressing cells. It also provides evidence that the mechanism of PKA modulation of Cav1.2 Ca2+ channels appears to differ in different cell types. Clearly, direct phosphorylation of Ser-1928 of the α1-subunit is not required for β-adrenergic regulation of Cav1.2 in the heart (4,7). However, this residue is required for β-adrenergic stimulation of Ca2+ channels in hippocampal neurons and for hyperglycaemia-induced stimulation of Ca2+ currents in arterial smooth muscle cells (8,9).

Despite compelling evidence for this novel mechanism, several questions remain: First, what is the role of Rad-dependent modulation of the cardiac L-type channel in intact cardiomyocytes, for example in cardiomyocytes expressing Rad with mutated PKA phosphorylation sites. Second, what is the relative importance of Rad versus modulation by direct phosphorylation of Ser-1700 (and Thr-1704), which has also been found to confer some of the PKA activation of L-type current in cardiomyocytes of Ser1700Ala mutant mice (5).

Despite these open questions, we are now getting close to understand the molecular mechanisms underlying the fight-or-flight response.

Comments by Jörg Striessnig, University of Innsbruck, Chair for NC-IUPHAR Subcommitee for Voltage-gated calcium channels, Liaison for NC-IUPHAR subcommittees on Voltage-gated ion channels

  1. Osterrieder W, Brum G, Hescheler J, Trautwein W, Flockerzi V, Hofmann F. (1982) Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature 298, 576–8.
  2. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renström E, Wietzorrek G, Berjukov S, et al. (2004) Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ J Clin Invest. 113: 1430–9.
  3. Yatani A, Codina J, Imoto Y, Reeves JP, Birnbaumer L, Brown AM. (1987) A G protein directly regulates mammalian cardiac calcium channels. Science 238, 1288–92.
  4. Lemke T, Welling A, Christel CJ, Blaich A, Bernhard D, Lenhardt P, et al. (2008) Unchanged beta-adrenergic stimulation of cardiac L-type calcium channels in Cav1.2 phosphorylation site S1928A mutant mice. J Biol Chem. 283, 34738–44.
  5. Fu Y, Westenbroek RE, Scheuer T, Catterall WA. (2014) Basal and beta-adrenergic regulation of the cardiac calcium channel Cav1.2 requires phosphorylation of serine 1700. Proc Natl Acad Sci U S A. 111, 16598–603.
  6. Brandmayr J, Poomvanicha M, Domes K, Ding J, Blaich A, Wegener JW, et al (2012) Deletion of the C-terminal phosphorylation sites in the cardiac beta-subunit does not affect the basic beta-adrenergic response of the heart and the Cav1.2 channel. J Biol Chem. 287, 22584–92.
  7. Liu G, Papa A, Katchman AN, Zakharov SI, Roybal D, Hennessey JA, et al. (2020) Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics. Nature 577, 695–700 [PMID: 31969708].
  8. Qian H, Patriarchi T, Price JL, Matt L, Lee B, Nieves-Cintrón M, et al. (2017) Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons. Sci Signal. 10 (463), pii: eaaf9659
  9. Nystoriak MA, Nieves-Cintrón M, Patriarchi T, Buonarati OR, Prada MP, Morotti S, et al. (2017) Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel Cav1.2 and vasoconstriction during acute hyperglycemia and diabetes. Sci Signal. 10(463), pii: eaaf9647

 

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Hot topics: Cannabinoid receptor stuctures

Posted on February 6, 2020 by guidetopharmacology — Leave a comment

Two new reports cover further aspects of cannabinoid receptor binding as defined using cryo-EM. These expand on previous reports of the structure of the human CB1 cannabinoid receptor with the antagonists taranabant and  AM6538 bound, and with the agonists MDMB-FUBINACA, AM11542 and AM841 bound. Previously reported also is the structure of the CB2 cannabinoid receptor with the antagonist AM10257 bound.

In the first report (1), a non-selective, high potency agonist WIN55212-2 was bound to a complex of the CB2 cannabinoid receptor with Gi to “complete the set” of agonist- and antagonist-bound versions of CB1 and CB2 receptors. The authors suggest marked similarities in the binding configuration of the agonist WIN55212-2 and the antagonist AM10257. Based on these structures, two novel ligands were generated; one predicted to be an agonist and the other an antagonist. The functional data supported these predictions, although both novel compounds were markedly less potent than their respective positive controls.

In the second report (2), agonist-bound versions of both CB1 and CB2 cannabinoid receptors complexed with Gi were also described to ‘complete and expand the set’. AM12033 is a novel nitrilodimethylheptyl analogue of THC with high affinity at both receptors. Structures using this compound were compared to CB1 receptors bound to the THC-like AM841. The authors suggest similar modes of interaction for agonists at the two receptors, supported by numerous examples of non-selective high potency agonists.

Modelling of the second intracellular loop in both reports suggested a structural basis for the CB2 receptor to couple poorly to Gs. Indeed, a single amino acid variation (L222 in CB1 and P139 in CB2 receptors) was highlighted in both studies and evidenced in the previous literature (https://www.ncbi.nlm.nih.gov/pubmed/23667597).

Comments by Prof. Steve Alexander (@mqzspa), University of Nottingham, UK

(1) Xing C. et al. Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G i Signaling Complex. Cell (2020) doi:10.1016/j.cell.2020.01.007 [PMID:32004460]

(2) Hua T. et al. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures. Cell  (2020) doi:10.1016/j.cell.2020.01.008 [PMID:32004463]

 

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Hot Topics: A brief update on coronaviruses

Posted on February 3, 2020 by guidetopharmacology — Leave a comment

The new respiratory coronavirus from Wuhan in China is causing intense research activity in the world. Viruses are evidently associated with respiratory infections ranging in severity from the common cold to pneumonia and death. More than 200 viral types have been associated with the common cold, of which 50% of infections are rhinovirus, but also respiratory syncitial virus, influenza – and coronaviruses, particularly human coronavirus-229E (HCoV-229E), which is ‘relatively benign’. Monocytes are relatively resistant to HcoV-229E infection, but rapidly invades, replicates in, and kills dendritic cells within a few hours of infection (Mesel-Lemoine et al., 2012) [1]. Dendritic cells are the sentinel cells in the respiratory tract, and plasmacytoid dendritic cells are a crucial antiviral defence via interferon production. Thus, these viruses can impair control of viral dissemination and the formation of long-lasting immune memory. The cellular receptor for HcoV-229E is CD-13 (aminopeptidase-N).
The cellular receptors for coronaviruses are critical for cell entry. Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and HCoV-NL63, bind to angiotensin converting enzyme2, ACE2, on ciliated cells in the respiratory tract, the crystal structure is known (Song et al., 2018) [2]. The SARS-CoV spike (S) glycoprotein (with S1 and S2 sub-units) on the outer envelope binds to ACE2, fusing viral and cellular membranes, triggering conformational transformations. Cleavage of the S1/S2 subunits by proteases is critical. Indeed, Simmons et al (2005) [3] showed that SARS-CoV infection involved receptor binding, conformational changes receptor binding and subsequent cathepsin L (and type II transmembrane serine proteases) proteolysis within endosomes – with inhibitors of cathepsin L preventing viral entry. SARS-CoV may lead to markedly elevated cytokine levels, leading to tissue damage, pneumonitis, and acute respiratory distress syndrome (ARDS). The spike proteins in SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) are crucial for host specificity and jumping between species, e.g. from bats to humans (Lu et al., 2015) [4], and also the recent cross-over to swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs (Zhou et al., 2018) [5]. There is intense interest in the complicated ways whereby coronaviruses engage with their target receptors, are activated and replicate. The rapid evolution of coronaviruses is critical as humans have little or no pre-existing immunity SARS- or MERS-CoV.

ACE2 has been identified as a potential receptor for the novel coronavirus that was identified as the cause of the respiratory disease outbreak in Wuhan in late 2019 (referred to as 2019 – nCoV by the WHO, or Wuhan coronavirus) [6,7 & 9]. 2019-nCoV is a betacoronavirus, and, in common with the SARS-CoV [8], the viral spike protein is postulated to engage ACE2 for viral entry [7]. The data presented by Letko and Munzter [7] is preliminary and has not been peer-reviewed, but a rapid pace of research is needed in the present circumstances. For example, in another recent, preliminary report, ACE2 receptor expression is highly expressed in type II alveolar cells (AT2) with much individual variation and the authors reported that the cells also expressed many genes involved in viral reproduction and transmission [10]. While these findings are preliminary, the rapid publications in bioRxiv and similar archives are crucial in what is now officially a global health emergency. This report is a hot topic in the IUPHAR/BPS Guide to PHARMACOLOGY (https://www.guidetopharmacology.org), and further underlines the importance of immunopharmacology and the IUPHAR Guide to IMMUNOPHARMACOLOGY (https://www.guidetoimmunopharmacology.org/immuno/index.jsp).

Comments by Prof. Michael Spedding, Spedding Reseach Solutions; Prof. Steve Alexander (@mqzspa), University of Nottingham; Dr. Elena Faccenda, University of Edinburgh; and Prof. Francesca Levi-Schaffer, The Hebrew University of Jerusalem.

Note from bioRxiv: bioRxiv is receiving many new papers on coronavirus 2019-nCoV.   A reminder: these are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

 

  1. Mesel-Lemoine M, Millet J, Vidalain PO, Law H, Vabret A, Lorin V, Escriou N, Albert ML, Nal B, Tangy F. A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes. J Virol. 2012 Jul;86(14):7577-87. doi: 10.1128/JVI.00269-12. Epub 2012 May 2. PubMed PMID: 22553325; PubMed Central PMCID: PMC3416289.
  2. Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog. 2018 Aug 13;14(8):e1007236. doi: 10.1371/journal.ppat.1007236. eCollection 2018 Aug. PubMed PMID: 30102747; PubMed Central PMCID: PMC6107290.
  3. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11876-81. Epub 2005 Aug 4. PubMed PMID: 16081529; PubMed Central PMCID: PMC1188015.
  4. Lu R, Wang Y, Wang W, Nie K, Zhao Y, Su J, Deng Y, Zhou W, Li Y, Wang H, Wang W, Ke C, Ma X, Wu G, Tan W. Complete Genome Sequence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) from the First Imported MERS-CoV Case in China. Genome Announc. 2015 Aug 13;3(4). pii: e00818-15. doi: 10.1128/genomeA.00818-15. PubMed PMID: 26272560; PubMed Central PMCID: PMC4536671.
  5. Zhou L, Sun Y, Lan T, Wu R, Chen J, Wu Z, Xie Q, Zhang X, Ma J. Retrospective detection and phylogenetic analysis of swine acute diarrhoea syndrome coronavirus in pigs in southern China. Transbound Emerg Dis. 2019 Mar;66(2):687-695. doi: 10.1111/tbed.13008. Epub 2019 Jan 9. PubMed PMID: 30171801.
  6. Gralinski LE, Menachery VD. Return of the Coronavirus: 2019-nCoV. Viruses. 2020 Jan 24;12(2). pii: E135. doi: 10.3390/v12020135. PubMed PMID: 31991541.
  7. Letko M, Munster V. Functional assessment of cell entry and receptor usage for lineage B β coronaviruses, including 2019-nCoV. bioRxiv 2020.01.22.915660; doi: 10.1101/2020.01.22.915660
  8. Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005 Sep 16;309(5742):1864-8. PubMed PMID: 16166518.
  9. Peng Z, Shi Z-L. (2020) Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. bioRxiv 2020.01.22.914952; doi: 10.1101/2020.01.22.914952
  10. Yu Zhao, Zixian Zhao, Yujia Wang, Yueqing Zhou, Yu Ma, Wei Zuo.Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov bioRxiv 2020.01.26.919985 doi: 10.1101/2020.01.26.919985
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Hot Topics: Cryo-EM structure of a selective T-type calcium channel blocker bound to the Cav3.1 voltage-gated calcium channel

Posted on January 7, 2020 by guidetopharmacology — Leave a comment

Nieng Yan’s group has now published the cryo-EM structure of the selective T-type Ca2+ channel blocker Z944 bound to the pore-forming α1-subunit of Cav3.1 T-type Ca2+ channels (1). This nicely adds to recent publications reporting of the high-resolution structures of L-type Ca2+ channel blockers (nifedipine, nimodipine, amlodipine, verapamil, diltiazem) bound to the rabbit Cav1.1 skeletal muscle Ca2+ channel (2) and to the model Ca2+ channel CavAb (Ca2+-selectivity engineered into the bacterial homotetrameric Na+-channel NavAb; 3, 4).

Together these three publications provide important insight into how small molecule channel blockers interact with their high affinity binding domains within Ca2+ channels. They also reveal a remarkable similarity between the core structures (i.e. the voltage-sensors and the pore domains) between not only the closely related Cav1.1 and Cav3.1 channels but also their bacterial ancestor CavAb.

Moreover, although some differences exist, the binding poses of L-type Ca2+ channel blockers in the mammalian Cav1.1 and the bacterial CavAb channel are very similar. In both structures verapamil and diltiazem bind within the central cavity, compatible with their pore-blocking properties predicted in functional studies. In contrast, dihydropyridines like nimodipine and nifedipine bind within a fenestration created by adjacent transmembrane S6 helices (IIIS6 and IVS6). These fenestrations penetrate the sides of the central cavities in both voltage gated Na+– and Ca2+ channels and connect them to the surrounding lipid bilayer of the plasma membrane (5). In accordance with functional studies, these dihydropyridines must therefore inhibit L-type channels by allosterically interfering with gating rather than pore block.

These findings raise the important question about how Z944 can selectively inhibit T-type Ca2+ channels. This drug is currently in clinical development for the treatment of epilepsy and neuropathic pain. It appears that Z944 bound to Cav3.1 combines the binding modes of both pore blockers and allosteric blockers. Its phenyl ring projects into the fenestration between repeats II and III (similar to nifedipine binding), whereas the other end of the molecule projects down through the central cavity to the intracellular mouth of the pore. A prominent interaction was found with lysine-1462, a residue unique for T-type channels. Its mutation to L-type residues reduced drug sensitivity in functional studies suggesting that it is one of the determinants for T-type selectivity.

Taken together the accumulating structural insight into drug binding and modulation will greatly facilitate structure-guided drug discovery. This may lead to new oral subtype-selective blockers of voltage-gated Ca2+ channels with therapeutic potential for the treatment of epilepsy (T-type), pain (T-type, N-type), tremor (T-type), primary aldosteronism (Cav1.3 L-type), progression of Parkinsons disease (Cav1.3, R-type) or rare neurodevelopmental disorders (Cav1.3 L-type) (6,7).

Comments by Jörg Striessnig, University of Innsbruck, Chair for NC-IUPHAR Subcommitee for Voltage-gated calcium channels, Liaison for NC-IUPHAR subcommittees on Voltage-gated ion channels

  1. Zhao, Y., Huang, G., Wu, Q., Wu, K., Li, R., Lei, J., Pan, X., and Yan, N. (2019). Cryo-EM structures of apo and antagonist-bound human Cav3.1. Nature. 576, 492–497 [PMID: 31766050].
  2. Zhao, Y., Huang, G., Wu, J., Wu, Q., Gao, S., Yan, Z., Lei, J., and Yan, N. (2019). Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+ Cell 177, 1495-1506 [PMID: 31150622].
  3. Tang, L., El-Din, T.M.G., Swanson, T.M., Pryde, D.C., Scheuer, T., Zheng, N., and Catterall, W.A. (2016). Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature 537, 117–121 [PMID: 27556947].
  4. Tang, L., Gamal El-Din, T.M., Lenaeus, M.J., Zheng, N., and Catterall, W.A. (2019). Structural Basis for Diltiazem Block of a Voltage-Gated Ca2+ Mol. Pharmacol. 96, 485–492 [PMID: 31391290].
  5. Payandeh, J., Scheuer, T., Zheng, N., Catterall, W.A., 2011. The crystal structure of a voltage-gated sodium channel. Nature 475, 353–358 [PMID: 21743477].
  6. Pinggera, A., and Striessnig, J. (2016). Cav 1.3 (CACNA1D) L-type Ca2+ channel dysfunction in CNS disorders. J. Physiol. (Lond.) 594, 5839–5849.
  7. Benkert, J., Hess, S., Roy, S., Beccano-Kelly, D., Wiederspohn, N., Duda, J., Simons, C., Patil, K., Gaifullina, A., Mannal, N., et al. (2019). Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease. Nat. Commun. 10, 5094. doi:10.1038/s41467-019-12834-x
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Hot Topics: Deciphering the crystal structure of the leukotriene receptor CysLT2 opens up for improved therapeutics

Posted on December 12, 2019 by guidetopharmacology — Leave a comment

Leukotrienes are lipid mediators of inflammation, initially recognized for their role in asthma, but also having potent effects in for example cardiovascular and neurological diseases as well as in cancer. The initial pharmacological classification of leukotriene receptors based on antagonist selectivity in smooth muscle was shown to be valid at the gene and protein levels. Following the recent description of the CysLT1 receptor structure, Gusach et al. now describe the crystal structures of the CysLT2 receptor in complex with dual CysLT1/CysLT2 receptor antagonists (1). This is an important advancement, since it allows to reveal specific characteristics of the two CysLT receptors in terms of ligand recognition and subtype selectivity. In this context, differences in the intracellular helix 8 emerge as particular subtype determinants, which may affect G-protein regulation and β-arrestin binding. The study by Gusach et al. (1) further provides structural insights into the changes in ligand binding and downstream signaling by CysLT2R disease-related single nucleotide polymorphisms (SNP) associated with asthma and cancer. The deciphering of the crystal structures for the CysLT1 and CysLT2 receptors will open up for the design of CysLT receptor antagonists with improved affinity/efficacy or subtype selectivity profiles. The insights into the CysLT receptor genome-structure-function relations may facilitate the prediction of disease associations and potentially further expanding the therapeutic indications of CysLT receptor antagonists.

Comments by Magnus Bäck, MD PhD, (@TransCardio), Karolinska Institutet and University Hospital, Stockholm, Sweden; Chairman NC-IUPHAR subcommittee on Leukotriene Receptors

(1) Gusach, A., Luginina, A., Marin, E. et al. Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors. Nat Commun 10, 5573 (2019) doi:10.1038/s41467-019-13348-2 [PMID:31811124]

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Hot Topics: New crystal structure of the muscarinic M5 receptor completes the set

Posted on November 28, 2019 by guidetopharmacology — Leave a comment

Muscarinic receptors consist of 5 G protein-coupled receptors which along with nicotinic ion channels mediate the effects of acetylcholine. Despite years of research on the role of muscarinic receptors in the brain and periphery the Muscarinic M5 receptor has stood out in contrast to M1 -M4 as one which we know little about. The M5 receptor has a unique and unusual distribution in the brain being enriched in mid brain dopamine neurons and in the cerebellum. A lack of selective chemical tools has hampered our ability to study the function of the receptor. Now Vuckovic et al. [1] have solved the X-ray crystal structure of the M5 receptor in complex with the non-selective antagonist tiotropium in the presence of a conformational stabilizing mutation. Since tiotropium was also used to solve the structure of several other muscarinic receptors a direct comparison can be made across the subtypes which will enable the design of selective tool compounds. Significant progress has been made in utilizing crystal structures to design selective orthosteric and allosteric ligands at this family of receptors. This final structure completes the set of muscarinic receptor structures solved and hopefully will pave the way to further understanding of the biology of M5 and its role in disorders such as drug addiction and depression.

Comments by Fiona H. Marshall, Discovery Research UK, MSD (@aston_fm)

(1) Vuckovic Z et al. (2019). Crystal Structure of the M5 Muscarinic Acetylcholine Receptor. Proc Natl Acad Sci USA, DOI: 10.1073/pnas.1914446116. [PMID: 31772027]

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Database Release 2019.5

Posted on November 15, 2019 by guidetopharmacology — Leave a comment

Our fifth and final database release of 2019 has been made and includes a number of minor content and website updates. Crucially, it comes at a time when we have just published our most recent database update in Nucleic Acids Research:

Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Southan C, Sharman JL, Campo B, Cavanagh DR, Alexander SPH, Davenport AP, Spedding M, Davies JA; NC-IUPHAR. (2019) The IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY. Nucl. Acids Res. pii: gkz951. doi: 10.1093/nar/gkz951 [Epub ahead of print]. [Full text]

and we have seen the publication of the 2019/20 Concise Guide to Pharmacology:

Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Buneman OP, Cidlowski JA, Christopoulos A, Davenport AP, Fabbro D, Spedding M, Striessnig J, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20 Br J Pharmacol. 176 S1: S1-S493. [Table of Contents]

JWS-SH-BJP-ConciseGuide-01-Pharmacology-1120x600px-BJP

Content Updates

Other Updates

Ligand list download

  • A new download button has been added to the ligand list pages. This enables users to download the specific ligand set they are viewingfor downloading specific sets of ligands (see image below).

Screenshot from 2019-11-15 10-04-37

PlasmoDB links

  • The IUPHAR/MMV Guide to Malaria Pharmacology now includes direct links from targets to PlasmoDB. The detailed target pages now clearly display the PlasmoDB accession for the target. The links are also included in the summary view of the target.

Upcoming presentations at:

We will be presenting on the Guide to Immunopharmacology and the Guide to Malaria Pharmacology at the following meeting over November and December

 

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Hot Topics: 3D structure of the full-length P2X7 receptor provides insight into factors controlling agonist potency and receptor desensitisation

Posted on October 7, 2019 by guidetopharmacology — Leave a comment

P2X receptors are ligand-gated cation channels for which ATP is the endogenous orthosteric agonist. Seven P2X subunits have been identified and they form trimers to produce at least twelve different receptor subtypes. The tertiary structure of several subtypes have been reported, but they all lack clear information on the conformation of the N- and C-terminal cytoplasmic domains because of the truncated constructs used and the flexibility of these domains. Now, McCarthy et al., (1) report single-particle cryo-EM images of the full-length rat P2X7 receptor in both apo (closed pore) and ATP-bound (open pore) states, which suggest why the affinity of this receptor for ATP is low, indicate how cysteine residues in the C-terminal control desensitisation and reveal a surprising guanine nucleotide binding site in the C-terminal.

The potency of ATP at P2X7 is three orders of magnitude lower than at other P2X subtypes. Whilst these new structures show some differences between the orthosteric ATP binding pocket of P2X7 and P2X3 receptors, these are unlikely to explain the great difference in ATP potency. Notably, however, the entrance to the pocket is much narrower in P2X7 (<11A° orifice) than in P2X3 (17A° orifice) receptors. This and any protein flexibility that opens and closes the entrance would decrease the time ATP spends in the binding pocket, so decreasing its affinity.

A unique feature of P2X7 receptors is an 18-amino acid long cytoplasmic region at the end of TM2 (named the C-cys anchor by the authors) that is cysteine-rich and which links TM2 to the cytoplasmic cap, a structural domain formed by N- and C-terminal residues that determines the rate at which P2X receptors desensitise. The present report shows that the C-cys anchor contains at least four cysteine residues and one serine residue that are palmitoylated and that the aliphatic chains extend into the plasma membrane, anchoring the receptor to the membrane. The authors speculate that this could keep the cytoplasmic cap in place and so limit P2X7 desensitisation. Consistent with this, the receptor, which is normally non-desensitising in the presence of ATP, desensitised rapidly and fully when the C-cys anchor was deleted or the cysteine residues removed by mutation.

A further unique feature of P2X7 receptors compared with other subtypes is the long C-terminal (~200 residues), which the authors term the cytoplasmic ballast. The images show for the first time that each receptor has three globular, wedge-shaped cytoplasmic ballasts, each of which hangs beneath the TM domain of an adjacent subunit. Intriguingly, each cytoplasmic ballast contains a dinuclear zinc ion complex and a high-affinity guanosine nucleotide binding site, the functions of which are unclear.

The P2X7 receptor is of particular therapeutic interest because it is cytotoxic due to its ability to activate the NLRP3 inflammasome and release pro-inflammatory cytokines. This study substantially extends our knowledge and understanding of its pharmacological and biophysical properties and forms the basis of further potential experiments designed to fully characterise how it functions.

Comments by Dr. Charles Kennedy, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde

(1) McCarthy et al. (2019). Full-length P2X7 structures reveal how palmitoylation prevents channel desensitization. Cell. https://doi.org/10.1016/j.cell.2019.09.017. [ScienceDirect: View Article]

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Official Launch of the Guide to MALARIA PHARMACOLOGY

Posted on September 26, 2019 by guidetopharmacology — 1 Comment

gtommv_bannerWe are delighted to announce the first full public release of the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY (abbreviated to GtoMPdb). This new web resource, designed specifically for malaria pharmacology, has been developed as a joint initiative between the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Medicines for Malaria Venture (MMV). It has been constructed as an extension to the parent Guide to PHARMACOLOGY database (GtoPdb) and incorporates new pharmacological content, including molecular targets in the malaria parasite and interaction data for ligands with antimalarial activity. In addition, a dedicated portal has been developed, in consultation with key opinion leaders in malaria research, to provide quick and focused access to these new data.

Screen Shot 2019-09-26 at 15.32.20The GtoMPdb portal homepage

A more detailed introduction to the project and a chronicle of technical developments can be found in our previous blog posts.

This initiative has enriched the GtoPdb and it is hoped will foster innovation by providing, in a single expert-curated database, results from antimalarial drug discovery programmes and the scientific literature. Following the lastest database release (2019.4), the Antimalarial targets family and the Antimalarial ligands family were updated and now contain a total of 30 P. falciparum (3D7) targets and 72 ligands annotated with antimalarial activity. The GtoMPdb has maintenance funding, ensuring new data curation will continue until June 2020.

We would like to take this opportunity to thank everyone involved in the project and for the helpful feedback we received during beta-testing of the portal. If you have any further feedback or queries about the resource please contact enquiries@guidetopharmacology.org

This project is supported by a grant awarded to Professor Jamie Davies at the University of Edinburgh by Medicines for Malaria Venture (MMV).

 

 

 

 

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Database Release 2019.4

Posted on September 18, 2019 by guidetopharmacology — Leave a comment

We are very pleased to announce our a new release of the IUPHAR/BPS Guide to Pharmacology. This version (2019.4) is the fourth this year and includes the first full-release of the IUPHAR/MMV Guide to Malaria Pharmacology.

Content Updates

GtoPdb now contains over 9,800 ligands, with around 7,450 having quantitative interaction data to biological targets. 1,442 of the ligands are approved drugs. The database contains over 1,700 human targets with curated interactions, with just over 1,500 of these having quantitative data. Full stats can be found on our About Page.

Here’s a brief summary of some of main curatorial updates:

  • The Lysyl oxidases family has been added to allow the GtoPdb to capture advance in medicinal chemistry and development of lysyl oxidase inhibitors. Lysyl oxidases are extracellular enzymes that are vital for cross-linking fibrillar elastin and collagens and for extracellular matrix stabilisation. LOX and LOXL2 are implicated in fibrosis, tumourigenesis, and metastasis, and are subsequently molecular targets for cancer drug discovery.
  • We have cross-referenced GtoPdb ligands against the World Health Organization (WHO) Model List of Essential Medicines, and now include this subset as a specific ligand category on our ligand list page. This classification is also displayed on ligand summary pages. Currently, 193 ligands in GtoPdb are on the WHO list.

Guide to Malaria Pharmacology (GtoMPdb)

We are delighted to officially launch the first full public release of the IUPHAR/MMV Guide to Malaria Pharmacology. GtoMPdb has been constructed in partnership with the Medicines for Malaria Venture (MMV), an organization dedicated to identifying, developing and delivering new antimalarial therapies that are both effective and affordable. This is in response to the global challenge of over 200 million cases of malaria and 400 000 deaths worldwide, with the majority in the WHO Africa Region.  It provides new pharmacological content, including molecular targets in the malaria parasite and interaction data for ligands with antimalarial activity.  We have pioneered curation of data from assays screening compounds against the whole organism, used routinely in antimalarial drug discovery.

A dedicated portal has been developed to provide quick and focused access to these new data and we have added direct links on the main GtoPbd home page.

home6

GtoPdb home page with new menu bar links to GtoMPdb.

In this database release these are the recent advancements made in the GtoMPdb.

  • The Antimalarial targets family and the Antimalarial ligands family have been updated, giving a total of 30 P. falciparum (3D7) targets and 72 ligands tagged as antimalarial in the database.
  • We have fixed the display of interactions to avoid duplicate rows – now data for a single target, ligand and species will appear together.

You can read more about the launch at this blog post.

Other Updates

Immunopharmacology content statistics

On the immunopharmaoclogy help page we have added a dynamic list of database content stats.

External links in Europe PMC

The GtoPdb has recently been included in the External Links service at Europe PMC (EPMC)  (https://europepmc.org/LabsLink). On EPMC pages, links to target and ligand entries have been added to the papers curated by GtoPdb that include a quantitative description of the ligand-target interaction. It is possible to retrieve all these references at EMPC by running an “Advanced Search” and selecting “IUPHAR/BPS Guide to Pharmacology” from the “External Links” drop-down list (LABS_PUBS:”1969″) as the cross-reference query. This currently gives 1,729 results, which can be further combined as Boolean-type queries against all other types of EPMC indexing including Bibliographic Fields, Filters, Data Links, External Links and Annotations.

empc

External Links for PMC:6452685 – showing links back to GtoPdb targets and ligands.

Bioschemas

We are also working with Bioschemas (http://bioschemas.org/) (35) to add schema.org semantic mark-up to GtoPdb, which will make it simpler for search engines to index the website. Our current focus is on implementing mark-up on all ligand summary pages, including properties from the Bioschemas MolcularEntity profile (https://bioschemas.org/specifications/drafts/MolecularEntity). A first version of the ligand mark-up has been added, but it remains a work in progress as we seek to refine it.

Posted in Database updates, Guide to Immunopharmacology, Guide to Malaria Pharmacology, Technical

Hot Topics: GPR139 as a potential target for increasing opioid safety

Posted on August 30, 2019 by guidetopharmacology — Leave a comment

The cross-talk between different G protein-coupled receptor signal-transduction pathways is an intriguing concept with important physiological implications [1]. A recent study by Wang et al. [2] has discovered that the actions of opioid drugs on the μ-opioid receptor (MOR) are negatively regulated by an interaction with the undercharacterized GPR139 receptor [3]. These findings implicate GPR139 as a potential target for increasing opioid safety.

The authors first identified opioid modulators using a transgenic C. elegans platform that were engineered to express the human MOR (tgMOR). Using a rapid behavioral readout to screen ∼2,500 mutagenized tgMOR worms, the authors identified ∼900 mutants with abnormal sensitivity to the opioid agonists morphine and fentanyl. In this paradigm, hypersensitive mutants recovered more rapidly from opioid-induced paralysis compared to the tgMOR animals. The authors focused on two mutants, one with homology to the L-type Ca2+ channel that is known to potentiate the nociceptive properties of opioids and the other frpr-13 that shares a phylogeny with the mammalian receptor GPR139. Furthermore, the opioid hypersensitivity in transgenic worms was reversed by the overexpression human GPR139, suggestive of a functional interaction between the receptors.

The authors then performed a variety of supporting in vitro functional assays in HEK293T cells that indicated GPR139 overexpression could attenuate or abolish MOR signaling and cell-surface expression. They also demonstrated that GPR139 and MOR were associating when co-expressed in this model system, although the relevance of this interaction in a native system awaits further investigation. Nevertheless, GPR139 and MOR were co-expressed in mouse neurons in brain regions implicated in opioid reward, analgesia and withdrawal. Moreover, a series of electrophysiological experiments using knockout mice indicated that GPR139 may offset the opioid-mediated inhibitory effects on neuronal firing.

On the basis of these compelling data, the authors then investigated the behavioural correlate of the GPR139 and MOR interaction. Although GPR139 knockout mice were ostensibly healthy, they exhibited consistently increased acute responses to morphine, including in a conditioned place preference paradigm as a measure of opioid reward, as well as in thermal and mechanical pain models. Equally, the GPR139 knockout mice exhibited fewer behavioural signs of withdrawal following the cessation of chronic opioid exposure. In a final set of experiments, the administration of a GPR139 surrogate agonist JNJ-63533054 led to a dose-dependent reduction in morphine analgesia in both pain paradigms in wild-type mice [4]. JNJ-63533054 also markedly suppressed the self-administration of morphine these mice. Strikingly, these effects were absent in the Gpr139−/− mice, strongly implicating GPR139 as a negative regulator of opioid response in vivo.

Taken together, these findings suggest that GPR139 could be pharmacologically targeted in a strategy to increase the safety and efficacy of opioid treatment, which is currently an area of widespread public interest. Intriguingly, this study builds on the previous identification of α-Melanocyte Stimulating Hormone (αMSH) as a potential endogenous ligand for GPR139 [5]. Given that αMSH is derived from the same precursor as another MOR ligand (β-endorphin), these findings may further indicate an important physiological interaction between these receptors. It will be of great interest to dissect the pharmacology of GPR139 activation, particularly in terms of potential therapeutic advantages over the direct inhibition of MOR.

Comments by Simon R. Foster, Postdoctoral Research Fellow at Monash University and David E. Gloriam (@David_Gloriam), Professor at University of Copenhagen and Head of GPCRdb.

(1) Selbie, L. A. & Hill, S. J. G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. Trends in pharmacological sciences 19, 87-93, (1998). [PMID: 9584624]
(2) Wang, D. et al. Genetic behavioral screen identifies an orphan anti-opioid system. Science (New York, N.Y.), eaau2078, (2019). [PMID: 31416932]
(3) Vedel, L., Nohr, A. C., Gloriam, D. E. & Brauner-Osborne, H. Pharmacology and function of the orphan GPR139 G protein-coupled receptor. Basic & clinical pharmacology & toxicology, (2019). [PMID: 31132229]
(4) Liu, C. et al. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine. Molecular pharmacology 88, 911-925, (2015). [PMID: 26349500]
(5) Nohr, A. C. et al. The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), alpha-, and beta-melanocyte stimulating hormone (alpha-MSH, and beta-MSH), and the conserved core motif HFRW. Neurochem Int 102, 105-113, (2017). [PMID: 27916541]

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Hot Topics: Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel

Posted on August 20, 2019 by guidetopharmacology — Leave a comment

In this report the Catterall laboratory succeeded in solving the high resolution structure of a voltage-gated Na+-channel (Nav) in its resting state (1). Why is this difficult and why is this important? It is difficult because Navs exist in the resting state only at very negative voltages but not at a zero membrane potential required for structural analysis by X-ray crystallography or cryo-EM. Accordingly, all high resolution structures of Navs, whether pro- or eukaryotic, have so far reported channels with the voltage-sensing domains in the depolarized state, i.e. the positively charges S4 helices of the voltage sensors moved “up” towards the extracellular side. Therefore it is not known how the activation gate of the ion pore (formed by the four S6 helices) is kept closed by the voltage sensor in its resting position, i.e. with the S4-helices “down”. Some predictions about how this might work was inferred from structural work on related voltage-gated ion channels (e.g in a TPC1 channel, 2) or from a study in which a chimeric Nav construct was trapped in a closed (“deactivated”) state by a toxin (3). The elegant work presented here by Wideschaisri and colleagues (1) directly addressed this important question by generating suitable mutants of the bacterial Nav, NavAb (4). One mutant (KAV mutation) was engineered to shift its activation threshold to much higher voltages thus holding the channel in the resting state also at 0 mV for structural studies. Moreover, they introduced disulfide crosslinks locking the voltage-sensor in the desired resting (S4 “down”) or activated (S4 “up”) state. The stabilization of these states in these mutants were verified in functional studies to ensure that the structural data have clear functional correlates. Analysis of the X-ray structures (and cryo-EM structure for the KAV mutant) provided important novel insight into the structural rearrangements associated with the transition from the activated/open to the resting/closed state. This includes changes of the helical structure of S4 associated with its striking inward movement of about 11.5 A compatible with a “sliding helix” model. Rearrangements of the four S4-S5 linkers were found to tighten the “collar” around the S5 and S6 segments thus keeping the pore closed.
All this was possible because they used the bacterial NavAb, for their experiments. This comes with the advantage that this channel exists as a tetramer of identical subunits and therefore the mutations are present in all four voltage-sensors. This also facilitated disulfide cross-linking, because these channels lack endogenous cysteines. The disadvantage of NavAb is that it does not reflect the more complex structure of eukaryotic Nav and voltage-gated Ca2+ channels (Cavs) in which all four voltage-sensing- and pore forming elements are different and are tethered together in a single molecule. Nevertheless, there is no doubt that this “sliding helix” model of electromechanical coupling will also apply to eukarytic Navs and Cavs. Understanding all the conformational rearrangements occurring between resting and activated channel states will provide new opportunities for the discovery of state-dependent and subtype-selective Nav- and Cav- channel blocking drugs.

Comments by Jörg Striessnig, University of Innsbruck

(1) Wisedchaisri, G., Tonggu, L., McCord, E., Gamal El-Din, T.M., Wang, L., Zheng, N., Catterall, W.A., 2019. Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel. Cell 178, 993-1003. doi: 10.1016/j.cell.2019.06.031. [PMID: 31353218]
(2) Kintzer, A.F., Green, E.M., Dominik, P.K., Bridges, M., Armache, J.-P., Deneka, D., Kim, S.S., Hubbell, W., Kossiakoff, A.A., Cheng, Y., Stroud, R.M., 2018. Structural basis for activation of voltage sensor domains in an ion channel TPC1. Proc. Natl. Acad. Sci. U.S.A. 115, E9095–E9104. doi: 10.1073/pnas.1805651115. [PMID: 30190435]
(3) Xu, H., Li, T., Rohou, A., Arthur, C.P., Tzakoniati, F., Wong, E., Estevez, A., Kugel, C., Franke, Y., Chen, J., Ciferri, C., Hackos, D.H., Koth, C.M., Payandeh, J., 2019. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell 176, 702-715.e14. doi: 10.1016/j.cell.2018.12.018. [PMID: 30661758]
(4) Payandeh, J., Scheuer, T., Zheng, N., Catterall, W.A., 2011. The crystal structure of a voltage-gated sodium channel. Nature 475, 353–358. doi: 10.1038/nature10238. [PMID: 21743477]

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Hot Topics: The atlas of aminergic GPCR mutagenesis

Posted on July 15, 2019 by guidetopharmacology — Leave a comment

G protein-coupled receptors (GPCRs) are an important family of signal-transducing membrane proteins capable of binding various types of ligands from the extracellular space and activating various signalling pathways inside the cell, rendering them one of the largest protein target families in pharmaceutical research [1]. Receptors of the aminergic GPCRs family are particularly rewarding drug targets as they are implicated in various disease areas, and structure-based drug design has enabled the understanding of ligand binding and function, and the development of more than 500 approved drugs targeting these receptors. Advances in structural biology allowed the determination of more than 300 crystal structures of more than 60 GPCR subtypes to date [2], however, these still represent only a small fraction of known receptor-ligand associations [3].

Site-directed mutagenesis (SDM) is a versatile and frequently employed tool in pharmacological investigations used to infer structural features of protein-ligand interactions [4]. Mutation studies complement structural information provided by crystal structures by defining the roles and relative importance of residues involved in binding, functional activity, and selectivity for ligand chemotypes which have not yet been co-crystallized with their receptors. Community-wide GPCR structure modelling challenges have shown that the best models could be constructed by careful incorporation of mutation and SAR data relating to ligand binding [5]. However, an integrated analysis of receptor and ligand structures and SAR, mutation data, and binding mode prediction has been so far lacking.

The study of Vass et al. can be regarded as a meta-analysis of the site-directed mutagenesis literature for aminergic G protein-coupled receptors [6]. Through an exhaustive database and literature search, the researchers from VU University Amsterdam, Polish Academy of Sciences, University of Copenhagen and Sosei Heptares have collected 6692 mutational data points for 34 aminergic GPCR subtypes of 8 species from 302 publications, covering the chemical space of 540 unique ligands from mutagenesis experiments. This large body of mutation data was also annotated with the structure-based GPCR residue numbering enabling a comparison of mutation effects across different GPCR subtypes and sub-families, and mapped onto the residue positions in the available aminergic crystal structures. Mutation effects were binned into four categories: increased effect, no effect, decreased, and abolished effect, and the data is presented in large overview tables for the five aminergic sub-families. For ligands which had not yet been co-crystallized with their respective receptors, the authors provide predicted binding modes using a combined docking and interaction fingerprint approach to rationalize the mutation effects in light of the ligand SAR.

For each receptor sub-family, a discussion of the known structural receptor-ligand interactions, the ligand chemical space, the structural determinants of receptor-ligand interactions from mutation studies in the amine, major, minor pockets, and the extracellular vestibule, and the possibility of mutation effect extrapolation is provided. The authors also discuss mutation effects of the same ligands across different receptors providing insights into the receptor specific determinants of ligand binding. Finally, an overview is provided of some applications, and the possibilities and limitations of using mutation data to guide the design of novel aminergic receptor ligands.

The authors have deposited the data on Zenodo and in the GPCRdb, and a KNIME workflow was also provided using the 3D-e-Chem KNIME nodes to ease further analysis of the data by the readers [7].

Comments by Chris De Graaf (@Chris_de_Graaf), Director Computation Chemistry, Sosei Heptares.

(1) Santos et al. (2017). A comprehensive map of molecular drug targets. Nat Rev Drug Discov. doi: 10.1038/nrd.2016.230. [PMIDs: 27910877]

(2) Munk et al. (2019). An online resource for GPCR structure determination and analysis. Nat Methods. doi: 10.1038/s41592-018-0302-x. [PMIDs: 30664776]

(3) Vass et al. (2018). Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends Pharmacol Sci. doi: 10.1016/j.tips.2018.02.004. [PMIDs: 29576399]

(4) a) Munk et al. (2016). Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol. doi: 10.1016/j.coph.2016.07.003. [PMIDs: 27475047] b) Arimont et al. (2017) Structural Analysis of Chemokine Receptor–Ligand Interactions. J Med Chem doi: 10.1021/acs.jmedchem.6b0130. [PMIDs: 28165741]. c) Jespers et al. (2018). Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms. Trends Pharmacol Sci. doi: 10.1016/j.tips.2017.11.001. [PMIDs: 29203139]

(5) a) Kufareva et al. (2011) Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure. doi: 10.1016/j.str.2011.05.012. [PMIDs: 21827947]; b) Kufareva et al. (2014). Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. Structure. doi: 10.1016/j.str.2014.06.012. [PMIDs: 25066135]

(6) Vass et al. (2019). Aminergic GPCR-Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data. J Med Chem. doi: 10.1021/acs.jmedchem.8b00836. [PMIDs: 30351004]

(7) (a) https://3d-e-chem.github.io/; (b) http://doi.org/10.5281/zenodo.58104

Posted in Hot Topics

Database Release 2019.3

Posted on June 13, 2019 by guidetopharmacology — Leave a comment

We have now made the third IUPHAR/BPS Guide to Pharmacology database release of 2019 (2019.3). It includes updates focussed on preparation for the next edition of The Concise Guide to PHARMACOLOGY (2019/20), due out later this year.

Content Updates

GtoPdb now contains over 9,600 ligands, with around 7,300 have quantitative interaction data to biological targets. 1,426 of the ligands are approved drugs. The database contains over 1,700 human targets, with just over 1,500 of these having quantitative interaction data. Full stats can be found on our About Page.

Here’s a brief summary of some of main curatorial updates:

  • The cereblon protein has been added as a new target. For simplicity it is included in the Enzymes section of the Guide, as it is an important component of the E3 ubiquitin ligase complex, although it has no intrinsic catalytic activity. Cereblon is included in the Guide as its binding by thalidomide class drugs has been identified as the molecular mechanism that underlies the teratogenicity of this drug class. We have included quantitative data for interactions between cereblon and the three approved thalidomide type drugs (thalidomide, lenalidomide and pomalidomide), as well as an Immunopharmacology comment and information about clinical variants in disease.
  • The neuromedin U receptor family has an updated detailed introduction.
  • Several ‘new to the GtoPdb’ corticotropin releasing factor-1 (CRF-1) receptor antagonists (ligand IDs 10375-10379), their receptor interaction data and histories as clinical candidates have been added, including verucerfont and pexacerfont.
  • Nudix hydrolase 7, an enzyme that is involved in peroxisomal CoA/acyl-CoA homeostasis, and the first reported covalent NUDT7 inhibitor (NUDT7-COV-1) were added.
  • The Guanyly Cyclases were reorganised. A new family, Receptor guanylyl cyclases (RGC) family, was created and the existing RGC family was renamed Transmembrane guanylyl cyclases (and added as a sub-family of the new family). Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase was also moved within this new family. The NPR-C (natriuetic peptide receptor 3) target was moved to the Transmembrane guanylyl cyclases family and the Natriuretic peptide receptor family removed entirely from the Catalytic receptor class.
  • We generated HELM annotation and SMILES for the small cyclic peptide apelin receptor agonist MM07 and these were submitted to PubChem. See reference PMID:25712721

Guide to Malaria Pharmacology (GtoMPdb)

Earlier this year we issue a blog post introducing the Guide to Malaria Pharmacology. This gives a good background to the project and illustrates how we plan to handle curation of this data and how we are developing the new portal that accesses the data.

Thursday 25th of April was World Malaria Day 2019 and to raise awareness we issued a blog post and a news release, in conjunction with Edinburgh Infectious Diseases and the School of Biological Sciences. These highlighted the release of the GtoMPdb and also provided an account of the long association malaria research has had with Edinburgh.

In this database release these are the recent advancements made in the GtoMPdb.

tcp_list

Screenshot showing antimalarial ligands with Target Candidate Profiles (TCPs)

Other Updates

ChEMBL Target Links

Following on from the update to these links in the last release, we’ve finished updating the various place across the GtoPdb site the link out to ChEMBL.

Site search

Our site-wide search now works using ‘*’ as a wildcard indicator at the end of a search string. This helps make our search behaviour more consistent with other web-resources.

Other minor updates

Posted in Database updates, Guide to Malaria Pharmacology, Hot Topics, Technical

Hot Topics: Time to FRET about GPCR activation dynamics?

Posted on May 16, 2019 by guidetopharmacology — Leave a comment

G protein coupled receptors (GPCRs) are crucial for the transduction of extracellular stimuli to the intracellular space. Upon activation, GPCRs undergo large conformational changes to engage transducers and stimulate intracellular responses. However, the kinetics of agonist induced GPCR conformational changes are relatively understudied. An exception to this is the class A rhodopsin receptor, which has a covalent agonist and fast (< 1ms) activation kinetics. In contrast, other GPCRs are thought to activate across the low to mid millisecond range [1]. For Class C GPCRs, which are distinct from class A receptors in that they contain large extracellular agonist binding domains and exist as obligate dimers, the site of agonist binding is >100Å from where the transducer interacts [2]. Class C GPCR activation involves both dimer rearrangement and activation of the 7-transmembrane (7-TM) domain, which are thought to occur over 20-200ms [3-5]. An outstanding question is whether the activation kinetics of rhodopsin are indeed faster than other GPCRs, or if previous experimental approaches lacked sufficient resolution to reveal fast kinetics in other receptor families.

To this end, Grushevskyi and colleagues have used FRET recordings to detect submillisecond activation dynamics of a prototypical class C GPCR, metabotropic glutamate receptor subtype 1 (mGlu1), demonstrating that mGlu1 undergoes two temporally distinct conformational changes upon activation [6]. Inter-subunit movements were detected by labelling the second intracellular loop of one protomer with CFP and the other with YFP. Intra-subunit changes detected by labelling each protomer with YFP in the second intracellular loop and CFP in the C-terminus. Synchronous activation of receptors was achieved via two complementary methods. UV-induced uncaging of glutamate in intact cells resulted in an increase in inter-subunit FRET and a decrease in intra-subunit FRET, which the authors believe represent movement of protomers towards each other and outward movement of TM6, respectively. Dimer rearrangement occurred with an average time constant of ~2ms, with 7TM conformational changes occurring approximately 10 times slower. Rapid solution exchange in outside-out Xenopus oocyte patches resulted in a similar two-step activation profile. Both methods revealed that initial mGlu1 dimer rearrangement occurs faster than previously reported [4,5], and is only loosely coupled to subsequent 7TM domain conformational changes. Receptor deactivation also occurred in two discrete steps, with inter-subunit rearrangements again preceding intra-subunit conformational changes. Occupancy of both binding sites was required for optimal activation and deactivation kinetics, as inter-subunit rearrangements in both directions were significantly slower in receptor mutants that only bind agonist in one protomer.

This study has revealed the existence of metastable intermediate activation states i.e. states in which the dimer rearrangement or the 7TM conformational changes exist in isolation. How these intermediate states influence mGlu1 signalling is unknown, as the fluorescently labelled mGlu1 dimers are unable to couple to G proteins [3]. Additionally, whether the intra-subunit FRET changes do indeed represent specific TM6 movements is somewhat ambiguous, given that the C-terminus to which CFP is attached is predicted to be highly flexible. However, should this activation mechanism be relevant and applicable across all Class C GPCRs, it may contribute to the complexity of Class C pharmacology. Allosteric agonists of Class C GPCRs bind to sites in the 7TM domain, activating receptors in the absence of orthosteric ligand [2], indicating that the 7TM-active state represents a physiologically relevant signalling conformation. These intermediate receptor activation states may also influence transducer coupling. Different orthosteric/allosteric ligand combinations shifting the balance between the various active states, stabilising unique conformations and engaging distinct downstream signalling pathways could play a part in the biased and probe dependent pharmacology apparent for many Class C GPCR ligands. Exploring multiple GPCRs with different orthosteric and allosteric ligand combinations is a crucial next step in understanding how the kinetics of receptor activation relates to ligand pharmacology. Understanding how drug-like compounds impact receptor activation kinetics and stabilise intermediate receptor states will likely play a large role in rational drug design programs going forward.

Comments by Shane D Hellyer (https://research.monash.edu/en/persons/shane-hellyer) and Karen J Gregory (https://research.monash.edu/en/persons/karen-gregory), Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Australia.

(1) Lohse M.J. et al. (2012). Fluorescence/bioluminescence resonance energy transfer techniques to study G protein-coupled receptor activation and signalling. Pharmacol Rev, 64: 299-336. [PMIDs: 22407612]
(2) Leach K & Gregory K.J. (2017) Molecular insights into allosteric modulation of Class C G protein-coupled receptors. Pharmacol Res, 116: 105-118. [PMIDs: 27965032]
(3) Hlacvackova V et al. (2012) Sequential inter- and intrasubunit rearrangements during activation of dimeric metabotropic glutamate receptor 1. Sci Signal, 5: ra59. [PMIDs: 22894836]
(4) Marcaggi P et al. (2009) Optical measurement of mGluR1 conformational changes reveals fast activation, slow deactivation, and sensitization. PNAS, 106: 11388-11393. [PMIDs: 19549872]
(5) Vafabakhsh R et al. (2015) Conformational dynamics of a class C G-protein-coupled receptor. Nature, 524: 497-501. [PMIDs: 26258295]
(6) Grushevskyi E.O. et al. (2019) Stepwise activation of a class C GPCR begins with millisecond dimer rearrangement. PNAS. pii: 201900261. doi:10.1073/pnas.1900261116. [Epub ahead of print] [PMIDs: 31023886]

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Posted in Hot Topics

World Malaria Day 2019: A New Guide to Malaria Pharmacology

Posted on April 22, 2019 by guidetopharmacology — 1 Comment

Thursday 25th 2019 is World Malaria Day and we’d like to highlight our new resource, currently under development, called The IUPHAR/MMV Guide to Malaria Pharmacology (GtoMPdb). Based in Edinburgh, this new resource is directed by Professor Jamie Davies and his team and funded by the Medicines for Malaria Venture (MMV).

Malaria and Edinburgh

Malaria and Edinburgh have a long association. This was marked most notably by the announcement by Patrick Manson, at a meeting of the British Medical Association (BMA) in Edinburgh in July 1898, of the discovery by Ronald Ross of the mosquito cycle of the malaria parasite, in a lecture on ‘The mosquito and the malaria parasite’. The first Nobel prize to be awarded to a British subject was awarded in 1902 to Ross for this discovery is now displayed in the Museum of Scotland in Edinburgh. He received the award for showing how the mosquito was the vector for the transmission of malaria. More about Malaria research in Edinburgh.

IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

The IUPHAR/MMV Guide to MALARIA PHARMACOLOGY (GtoMPdb) database portal is a new extension to the existing Guide to PHARMACOLOGY database (GtoPdb). GtoMPdb is being developed as a joint initiative between Medicines for Malaria Venture (MMV) and the International Union of Basic and Clinical Pharmacology (IUPHAR), with the aim of adding curated antimalarial data to GtoPdb and providing a purpose-built portal that is optimized for the malaria research community.

The parent Guide to PHARMACOLOGY database (GtoPdb) has been extended to incorporate the additional information required to describe the activity and target interactions of antimalarial compounds. It provides a searchable database with quantitative information on Plasmodium molecular targets and the prescription medicines and experimental drugs that act on them. The development of this resource is important because until now there has been no single purpose-built portal into open access, expert curated information on Plasmodium molecular targets and the antimalarial compounds that act on them, including approved drugs, clinical candidates and research leads. This initiative will facilitate access by the malaria research community to lead, target and efficacy data integrated from disparate global R&D efforts.

More information about IUPHAR and MMV, and the project can be found here: https://www.guidetomalariapharmacology.org/malaria/gtmpAbout.jsp.

This blog post gives more detailed information about the development of GtoMPdb.

See also the Edinburgh Infectious Disease news page.

Expert Advisory Committee for the IUPHAR/MMV Guide to Malaria Pharmacology project

David R. Cavanagh, UK (https://www.ed.ac.uk/profile/dr-david-cavanagh)
Mark J. Coster, Australia
Michael P. Pollastri, USA
Laurent Rénia, Singapore
J. Alexandra Rowe, UK (http://alexrowe.bio.ed.ac.uk/)
Chris Swain, UK
Matthew H. Todd, UK
Elizabeth A. Winzeler, USA

Scientific Advisors for IUPHAR/MMV Guide to Malaria Pharmacology project

Jeremy N. Burrows, Switzerland
Brice Campo, Switzerland
Stephen P.H. Alexander, UK
Anthony P. Davenport, UK
Jamie A. Davies, UK
F. Javier Gamo, Spain
Michael Spedding, France
Stephen A. Ward, UK

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Posted in Guide to Malaria Pharmacology