IUPHAR review 100 in Pharm Revs and review 21 in BJP

Two new IUPHAR reviews have been published online in January 2017.

The first is the 100th in Pharmacological Reviews, a review on the nomenclature and properties of Calcium-Activated and Sodium-Activated Potassium Channels by Kaczmarek et al. For database entry click here.

The second is the 21st review in the British Journal of Pharmacology, an article on the evolution of RGS (Regulators of G protein signaling) proteins as drug targets by Benita Sjögren. For database entry click here.

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Posted in Publications

Hot topics: The orphan GPR139 receptor is activated by peptides

GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression in the striatum and hypothalamus, regions regulating locomotion and metabolism, respectively, and it has therefore been suggested as a potential target for Parkinson’s disease and metabolic syndrome. Surrogate ligands have been published by Lundbeck A/S [1], Jansen R&D [2], Takeda Pharmaceuticals [3], as well as the University of Copenhagen (Gloriam group). In a new publication, the latter group describe the first combined structure-activity relationships of all surrogate agonist, and a common pharmacophore model for future ligand identification and optimization [4].

The physiological agonist of GPR139 is still elusive. GPR139 has previously been shown to be activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively) [5,6], as well as di-peptides [5]. A new publication shows that the endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone and α- and β-melanocyte stimulating hormone in the low micromolar range. In addition, a potentially novel subpeptide (from consensus cleavage site) represents the most potent putative endogenous activator, so far (EC50 value of 600 nM) [7]. Together, these results indicate that GPR139 is a likely to be a peptide receptor that could act as a secondary target for melanocortin peptides or a yet undiscovered physiological ligand.

[1] Shi, F. (2011). Discovery and SAR of a series of agonists at orphan G protein-coupled receptor 139. ACS Med. Chem. Lett. 2, 303–306. doi:10.1021/ml100293q. PMID: 24900311

[2] Dvorak, C. (2015). Identification and SAR of glycine benzamides as potent agonists for the GPR139 Receptor. ACS Med. Chem. Lett. 6, 1015–1018. 10.1021/acsmedchemlett.5b00247. PMID: 26396690

[3] Hitchchock, S. (2016). 4-oxo-3,4-dihyroI-1,2,3-benzotriazine modulators of GPR139. US Patent US2016/0145218 A1. Takeda Pharmaceutical Company Limited

[4] Shehata, M.A. (2016). Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep. 6, 36681. doi:10.1038/srep36681. PMID: 27830715

[5] Isberg, V. et al. (2014). Computer-aided discovery of aromatic L-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139. J. Chem. Inf. Model. 54, 1553–1557. doi: 10.1021/ci500197a. PMID: 24826842

[6] Liu, C. (2015). GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine. Mol. Pharmacol. 88, 911–925. doi: 10.1124/mol.115.100412. PMID: 26349500

[7] Nøhr, A.C. et al. (2016). The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW. Neurochem. Int. 102, 105–113. doi: 10.1016/j.neuint.2016.11.012. PMID: 27916541

Comments by David E. Gloriam and Anne Cathrine Nøhr Jensen (Department of Drug Design and Pharmacology, University of Copenhagen)

Posted in Hot Topics

Hot topics: X-ray crystallographic study defines binding domains for Ca2+ antagonist drugs and their molecular mechanism of action

This year witnessed a tremendous progress in our understanding of the structure-function relationship of voltage-gated Ca2+ channels. This is based on the cryo-electron microscopy structure of the rabbit Cav1.1 Ca2+ channel complex at a nominal resolution of 3.6 Å ([1] see Hot Topics Sep 20, 2016) which is now nicely complemented by a study defining the binding domains for Ca2+ antagonist drugs and their molecular mechanism of action at atomic resolution [2]. The authors took advantage of their elegant previous work solving the structure of bacterial Na+ channels (NavAb) by X-ray crystallography both in a pre-open and inactivated state [3,4]. They also engineered Ca2+ selectivity into its selectivity filter (“CavAb”, [5]) and found high affinity inhibition by the different chemical classes of Ca2+ antagonist drugs similar to L-type Ca2+ channels. Since CavAb assembles as a tetramer, this channel also replicates the four domain structure of the pore-forming subunit of voltage-gated Ca2+ and Na+-channels: an excellent model to investigate the drug-channel interaction at atomic resolution was now at hand.
As predicted for L-type Ca2+ channel α1-subunits by photoaffinity labeling studies 25 years ago [6], dihydropyridines (DHPs, e.g. amlodipine, nimodipine) bind to an extracellularly exposed intersubunit crevice formed by neighbouring S6 helices and the P-helix of the selectivity filter. Drug binding displaces an endogenous lipid molecule in this site. Interestingly, DHP binding induces a conformational changes which breaks the fourfold symmetry of the channel. As a consequence only one molecule can occupy the channel with high affinity and the Ca2+ interaction with the selectivity filter also changes. This results in a higher affinity for Ca2+ ions revealing an intriguing mechanism of action for these drugs: rather than directly blocking the pore, they enhance Ca2+ affinity for the pore such that Ca2+ itself gets stuck in the ion conducting pathway. Therefore DHPs do the opposite of what would be intuitively expected for a “Ca2+ antagonist”, namely preventing Ca2+ interaction with the channel. Instead, they allosterically enhance Ca2+ binding.
In contrast, and also in agreement with photoaffinity labeling and mutational studies phenylalkylamines (PAAs, e.g. Br-verapamil) bind in the central cavity on the intracellular side of the selectivity filter also disrupting fourfold symmetry. Since it is known that PAAs access this site preferentially when the channel opens its intracellular mouth upon activation this nicely explains their known frequency dependent inhibition. Unlike DHPs these drugs bind within the pore and thus must act as pore blockers thus satisfying the term “Ca2+ antagonist”.
This work from the Catterall lab must be regarded as a milestone in Ca2+ channel research. It not only revealed the mechanism of action of one of the most prescribed classes of cardiovascular drugs but also brings us much closer to predicting structural features of new generations of Ca2+ antagonists with high selectivity for different isoforms of voltage-gated Ca2+ channels. Within the L-type Ca2+ channel family this could be relevant for discovering Cav1.3–selective drugs as potential therapeutics for neuroprotection in Parkinson’s disease and neuropsychiatric disorders, such as autism (7).

[1] Wu et al (2016). Structure of the voltage-gated 2+ channel Cav1.1 at 3.6 Å resolution.
Nature 537:191-196. [PMID 27580036]
[2] Tang et al. (2016). Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature 537, 117–121 [PMID 27556947]
[3] Payandeh et al. (2011). The crystal structure of a voltage-gated sodium channel. Nature 475, 353–358 [PMID 21743477]
[4] Payandeh et al. (2012). Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature 486, 135–139 [PMID 22678296]
[5] Tang et al. (2014). Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature 505, 56–61 [PMID 24270805]
[6] Catterall and Striessnig (1992). Receptor sites for Ca2+ channel antagonists. Trends Pharmacol Sci 13, 256–262 [PMID 1321525]
[7] Ortner and Striessnig (2016). L-type calcium channels as drug targets in CNS disorders. Channels 10: 7–13 [PMID 26039257]

Comments by Jörg Striessnig (Department of Pharmacology and Toxicology – Institute of Pharmacy, Universität Innsbruck)

Posted in Hot Topics

GtoImmuPdb: technical update December 2016


Our final technical update for 2016 covers our v2.0 alpha-release, presentation at Pharmacology 2016 and future plans.

An early synopsis of the project can be found in this blog post. Previous technical blogs are available for February, MayAugustSeptember & November 2016.

Development Progress

Alpha-Release v2.0


The menu-bars have been further development to include Processes and Cell Types. This basically extends the menu bar to have direct links to the new data types in GtoImmuPdb. The About and Resources menu items have been modified to make them specific to GtoImmuPdb. The ultimate aim of these developments is to make navigation through GtoImmuPdb user-friendly and logical. This will continue to be developed as we gather feedback. 

Documentation and Tutorial

The documentation and user-guide tutorial were both updated upon v2.0 release.

Ligand List pages

We have developed the ligand list pages (which are linked to from the portal ‘ligand’ panel) to include an immuno tab that when selected lists all ligands tagged in the database as being included in GtoImmuPdb. The page now has a toggle button to switch between the GtoImmuPdb and GtoPdb views. We have also put in place a new ‘immuno ligand’ icon, to be displayed in the table with the other icons when the ligand has been tagged in GtoImmuPdb.

Ligand pages

We have extended the ligand pages to contain a new ‘Immunopharmacology’ section (with in the Summary tab). This contains any specific immunopharmacology comments specific to the ligand.

Pharmacology 2016

During December it was an privlege to be able to attend the BPS Pharmacology 2016. We not only presented a poster describing the Guide to IMMUNOPHARMACOLOGY, but were also given the opportunity to present this as a 2-miunute, one slide, flash poster presentation.  The session was well attended and both the poster and presentation well received.

View poster on slideshare 

View presentation on slideshare

Other Development and Next Steps

The submission tool has been extended to incorporate ligand to disease associations. This is one of the first steps to fully incorporating disease association into GtoImmuPdb. These developments accompany additions to the database schema which now contains new tables to store these associations. Our expectation is to extend the schema and submission tool to also capture target-disease associations.

There are some disease terms in the database already, mostly linked to OMIM, the Disease Ontology or Orphanet. While these data resource may be adequate for annotating and describing immunological diseases and related diseases, we are exploring whether to include ICD disease classifications. Our aim is to have some GtoImmuPdb disease association in place prior to the beta-release in Spring 2017, but we are keeping this under-review.

In the next couple of months we will also be improving the current display of comments and references linked to new data types (processes and cell-types).  We will also be incorporating references to the ligands tagged in GtoImmuPdb, and surfacing their display.

This project is supported by a 3-year grant awarded to Professor Jamie Davies at the University of Edinburgh by the Wellcome Trust (WT).

Posted in Guide to Immunopharmacology, Technical

Hot topics: Will the real splice variants please stand up?

The number of alternative mRNA splice forms that map to human protein coding loci has increased to the point that nearly all proteins have such associated database records. This gives rise to the paradox that the gene build pipeline from the latest Ensembl GRCh38 reference genome assembly indicates 19,919 protein coding loci (which shrinks to 19,022 with HGNC annotation stringency) but 198,002 transcripts (i.e. nearly 10 transcripts per protein). Their is no question that a small number of these alternative splice forms, AS, (plus alternative initiations) have not only been verified to exist as proteins, have some kind of alternative biochemical functions and are also of pharmacological importance [1].  Notwithstanding, compared to the massive transcript profiling that RNAseq now provides routinely, experimentally verifying AS existence at the protein level at large scale is extremely difficult. This is because it can only be done by splice form specific antibodies, western blots detecting different size forms, top down proteomics (i.e. intact mass measurement) or the detection of alternative exon-specific trypic peptides. A recent  review [2] proposes that expanding data sets from the latter approach are consistently detecting only single quantitatively dominant protein isoforms from each locus. The provocative inference is that the vast majority of the 200K odd predicted and/or verified alternative mRNA transcripts are not actually translated into proteins.  This can be seen as an interesting methodological detection “gulph” between RNAseq and MS-proteomics.  However, their has been previous support for the “single isoform” idea on the basis of transcript data alone [3]. An ancillary conclusion from this paper, generally overlooked in terms of its significance, was that when CDS length was taken into account approximately 50% of major transcripts did not corresponding to the ‘canonical’, max-exon, transcript as annotated in Swiss-Prot. This crucial topic is further discussed in [4].

[1] Bonner, T.I. (2014). Should pharmacologists care about alternative splicing? IUPHAR Review 4. Br J Pharmacol. Mar;171(5):1231-40. doi: 10.1111/bph.12526. PMID: 24670145.

[2] Tress et al. (2016). Alternative Splicing May Not Be the Key to Proteome Complexity. Trends Biochem Sci. Sep 16. doi: 10.1016/j.tibs.2016.08.008. PMID: 27712956.

[3] Gonzàlez-Porta et al. (2013). Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene. Genome Biol.  Jul 1;14(7):R70. doi: 10.1186/gb-2013-14-7-r70. PMID: 23815980.

[4] Will the real cannoical protein please stand up.

Comments by Chris Southan

Posted in Hot Topics

GtoImmuPdb: technical update November 2016


During October we have made the first alpha-release (v1.0) of the Guide to IMMUNOPHARMACOLOGY. This blog post summarises some of the main features of the release and work on the documentation.

This first release marks an important step towards the public deployment of the first beta-release of GtoImmuPdb, scheduled for Spring 2017. We expect to make further alpha-releases over the next few months, as additional features are added.

An early synopsis of the project can be found in this blog post. Previous technical blogs are available for February, May, August & September 2016.

Development Progress

Alpha-Release v1.0

The portal has its own unique branding (header bar, logo and colour scheme) to distinguish it, but retains many of the layout features from the main GtoPdb site. This consistency should help users already familiar with GtoPdb to orientate themselves with the new GtoImmuPdb.


Screenshot of the GtoImmuPdb Portal, alpha-release v1.0

The portal provides a starting-point for accessing data in GtoImmuPdb, tailored to the requirements of users with a specific interest in immunopharmacology. Browsing by target, process and cell-type have been implemented in the alpha_v1.0 release. Ligands can be browsed, but there isn’t yet a immuno specific view for the results.

The portal and other pages with the GtoImmuPdb view toggled on will display a specific Guide to IMMUNOPHARMACOLOGY header and menu-bar. A consistent feature on the GtoImmuPdb pages is a ‘toggle’ button that enables the user to switch out to the standard GtoPdb view (and back).


Family page on GtoImmuPdb, showing new header and toggle button (a key feature of GtoImmuPdb)

Alpha-Release v1.0 Documentation

The main area of development over October 2016 has been to prepare the documentation for the alpha-release. These provide an explanation of the features included, how data was obtained and curated and how to use the site. Detailed release notes have been prepared, which will be incrementally added to or appended to on subsequent releases. They cover the following main sections:

  • GtoImmuPdb portal
  • Receptor Family pages
  • Family Pages
  • Detailed Target pages
  • Immuno Process Association List pages
  • Immuno Cell Type Association List pages
  • Search
  • Database Development

Documentation has also been prepared that gives details on how the data for both the process and cell type associations has been obtained. This includes a detailed spreadsheet on the full GO annotations, obtained via UniProt that form the basis of the immuno process associations.

We have also prepared a tutorial document that is a guide to navigating from the new portal, to access GtoImmuPdb data and understand the new GtoImmuPdb pages.

Alpha-Release v1.0 Data

GtoImmPdb uses the same underlying database as GtoPdb. This is has been extended to include and integrate GtoImmPdb data. The primary data-types of interest to GtoPdb, that have been addresses so far, are processes and cell-types. The database schema has been extended to accommodate these data-types and to associate them with targets in the database.

Immuno Process Data

GtoImmuPdb has defined its own set of top-level immunological process categories against which targets in the database can be annotated and which form the basis of organising, navigating and searching for immunological processes and associations.

These categories are:

  • Immune system development and differentiation
  • Proliferation and cell death
  • Production of signals and mediators
  • Regulation and responses to signals
  • Migration and chemotaxis
  • Cell-mediated immunity
  • Inflammation

We have associated sets of Gene Ontology (GO) terms with each of these categories. This enables us to auto-curate targets annotated to any of those terms (or their children) by GO into our top-level immunological categories. GO data is obtained via an OBO file (http://purl.obolibrary.org/obo/go.obo) for the ontology, which is edited to restrict it to immuno-specific terms. We auto-curate targets to the top-level process terms by using GO annotation information from UniProt. Through UniProt, targets were selected that were annotated to the subset of GO terms and also cross-referenced in GtoPdb. This gave a total of 1,855 annotation to 401 targets.

The table below summaries the unique targets (UniProt) annotated under each category

GtoImmPdb ‘High-Level’ Process Distinct UniProt
Immune System Development and Differentiation 124
Proliferation and Cell Death 33
Production of Signals and Mediators 74
Regulation and Responses to Signals 355
Migration and Chemotaxis 81
Cell-Mediated Immunity 99
Inflammation 261

Provision has been made in the database schema to capture curator comments against process information and annotations and the design is fully-adaptable to future changes.

Cell Type Data

The Cell Ontology provides the formalised vocabulary against which we annotated target to cell type associations. GtoImmuPdb has defined its own set of top-level immunological cell type categories against which targets in the database can be annotated and which form the basis of organising, navigating and searching for immunological cell types and associations.

These categories are:

  • pro-B-lymphocytes, B lymphocytes & Plasma cells
  • T lymphocytes (alpha-beta type) and their immediate progenitors
  • T lymphocytes (gamma-delta type) and their immediate progenitors
  • Natural Killer (NK) cells
  • Polymorphonuclear leukocytes (neutrophils, eosinophils, basophils)
  • Mononuclear leukocytes (syn: monocytes) (macrophages, dendritic cells, Kupffer cells)
  • Mast Cells
  • Innate Lymphoid Cell (added November 2016)

We have assigned one or more Cell Ontology terms to each of these categories. The assigned CO terms represents the highest level parent term(s) within the ontology for that category. For the purposes of annotation, it is these CO terms and their children that can be used when annotating a target to a given category. The exception is innate lymphoid cells which at present are not defined and included in the Cell Ontology.

Other Developments & Next Steps

Fixes have been made to out submission tool to include the ability to add/remove cell type categories and to add definitions/description of them.

Our focus in the next month is to develop the ligand browse landing pages (accessed via Ligand panel on the portal home), and add in icons to highlight immuno-flagged ligands throughout the main GtoPdb site.

We also want to develop the menu-bar navigation for GtoImmuPdb, as this will be important for the beta-release.

This project is supported by a 3-year grant awarded to Professor Jamie Davies at the University of Edinburgh by the Wellcome Trust (WT).

Posted in Technical

GtoPdb Ligands in PubChem

GtoPdb and  its precursor IUPHAR-DB have been capturing the structures of pharmacologically relevant ligands since 2005.  The fig.1. snapshot below  shows the approved drug section of our eight-category ligand classification

As an active collaboration with the  PubChem team, we have submitted our ligand records for every GtoPdb release since  2012.  For the current release of 2016.4 the query  (“IUPHAR/BPS Guide to PHARMACOLOGY”[SourceName])   retrieves 8674 Substance Identifiers (SIDs)  and  6565 Compound Identifiers (CIDs). The excess of 2109 SIDs is accounted for by antibodies, small proteins and large peptides that cannot form CIDs.  At just over 92 million CIDs from 473 sources, a range of property filters and full Boolean operations for combining query sets,  PubChem provides an opportunity to “slice and dice” our ligand set in detailed, comparative  and informative ways.  A set of results is shown below.


The utilities of these intersects are outlined below (in order of counts):

  1. CNER refers to “Chemical Named Entity Recognition” for the automated extraction of chemistry from patents by sources submitting to PubChem (of which SureChEMBL is the largest at 16.3 million). This means that users can track-back most of our ligands to early  patent filings that can often include more SAR than eventually appeared in the papers.
  2. Our low overlap with DrugBank indicates both sources are complementary in bioactive compound selection (i.e. the OR union is 12605)
  3. The possibility of sourcing purchasable compounds is important for experimental pharmacologists. From the 64 million vendor structures in PubChem we have nearly an 80% overlap and similarity searches may pick up analogues where there is no exact match.
  4. The “BioAssay active” tag overlaps extensively with ChEMBL entries but users can check for a range of activities for a ligand that maybe additional to the values we have extracted from selected papers.
  5. The MeSH term “pharmacological action” is useful but our impression is that NLM is falling behind in the PubChem indexing of this term.
  6. PDB ligand structures are valued database cross-references for many reasons.
  7. We have introduced a new feature that allows users to retrieve just our 1291 approved drug SID entries (Query “approved[Comment] AND “IUPHAR/BPS Guide to PHARMACOLOGY”[SourceName]”). The “PubChem Same Compound” select  then generates 1174 small-molecule CIDs. This facilitates different types of comparative analysis between drug lists.
  8. As expected, our overlap with ChEMBL structures is high but we have captured 1147 structures not in this source, mainly due to different journal capture and shorter release cycles.
  9. The selection “unique to GtoPdb” indicates those CIDs where we are the only source in the whole of PubChem. These are predominantly novel structures we have extracted from papers but in some cases we have selected a different structure from other sources.
  10. There may be interest in which pharmacologically active peptides we have CIDs for. A simple Mw-cut isolates 178 entries

In regard to 7) a snapshot from our list of approved drugs is shown below




Posted in Uncategorized