Database Release 2023.3

Posted on November 29, 2023 by guidetopharmacology — 1 Comment

The latest release of the IUPHAR/BPS Guide to Pharmacology database was made on 29th November 2023. This database release is version 2023.3, and is the third release this year. The following blog post gives details of the key content updates and website changes. GtoPdb now contains:

3,056 human targets, 1,715 of which have curated quantitative ligand interactions.
12,344 ligands, 9,072 of which have curated quantitative target interactions.
1,956 approved drugs, 1,117 with curated quantitative interactions.
Clinical use summaries for over 3,596 ligands of which 1,947 are approved drugs.
A total of 20,338 curated binding constants
Data curated from just over 44,000 references

NAR Publication and Database Report

In October 2023 our latest NAR Database Issue update was published:

Harding SD, Armstrong JF, Faccenda E, Southan C, Alexander SPH, Davenport AP, Spedding M, Davies JA. (2023) The IUPHAR/BPS Guide to PHARMACOLOGY in 2024. Nucl. Acids Res. 2023 Oct 28:gkad944. Online ahead of print. doi: 10.1093/nar/gkad944. [Full text]. PMID: 37897341.

In this update we report on recent developments to the resource and describe expansion in content over the six database releases made during the last two years. The database update section of this paper focuses on two areas relating to important global health challenges. The first, SARS-CoV-2 COVID-19, remains a major concern and we describe our efforts to expand the database to include a new family of coronavirus proteins. The second area is antimicrobial resistance, for which we have extended our coverage of antibacterials in partnership with AntibioticDB, a collaboration that has continued through support from GARDP.

In November, our latest Database Report became available, covering in more detail the work we have undertaken in terms of curation and development, alongside usage statistics in the last six months GtoPdb_Database_Report_Nov_2023.pdf. Our report is accessible via our Zenodo repository: https://doi.org/10.5281/zenodo.10078018

Curation Update

Targets

New targets since Release Version 2023.2: We have curated a range of new targets and we highlight novel ligands that modulate their functions, and any therapeutic potential associated with pharmacological target manipulation.

TID	Family	Gene	Name	Comment
3248	Lipid transfer/lipopolysaccharide binding proteins	CETP	cholesteryl ester transfer protein	A range of inhibitors with interaction data (e.g. anacetrapib, evacetrapib, dalcetrapib, obicetrapib): clinical potential for atherosclerotic cardiovascular disease & other dyslipidemias
3249	Carnitine palmitoyltransferases	CPT1A	carnitine palmitoyltransferase 1A	2 inhibitors with interaction data (teglicar, etomoxir); oncology potential
3250	Carnitine palmitoyltransferases	CPT1B	carnitine palmitoyltransferase 1B	1 inhibitor interaction (teglicar);; oncology potential
3251	Carnitine palmitoyltransferases	CPT1C	carnitine palmitoyltransferase 1C	No ligands identified
3252	Carnitine palmitoyltransferases	CPT2	carnitine palmitoyltransferase 2	2 inhibitors with interaction data (teglicar, compound 16 [PMID: 17585909]); oncology potential
3253	Hydrolases & Lipases	PNPLA2	patatin like phospholipase domain containing 2	Potential of lipase inhibitors to contribute to antiviral effects for RNA viruses, plus one inhibitor with interaction data for atglistatin. Also curated new inhibitors for other lipases (LIPE compound 41 [PMID: 15026062], MAGL & FAAH CAY10499.
3254	E3 ubiquitin ligase components	ZBTB25	zinc finger and BTB domain containing 25	CoV Mpro ubiquitination and degradation (= ?antiviral activity)
3255	Protein tyrosine phosphatases non-receptor type (PTPN)	PTPN2	protein tyrosine phosphatase, non-receptor type 2	dual PTPN1/2 inhib compound 182 [PMID: 37500611], oncology
3256	Diacylglycerol kinases	DGKA	diacylglycerol kinase alpha	dual inhibitor BMS-502 promotes immune stimulation (T cells); potential upregulation of anti-tumour immune response
3257	Diacylglycerol kinases	DGKZ	diacylglycerol kinase zeta	dual inhibitor BMS-502 promotes immune stimulation (T cells); potential upregulation of anti-tumour immune response
3258	Hydrolases & Lipases	NEU2	neuraminidase 2	regulation of cellular glycans repertoire. 2 novel inhibitors/experimental tools: compound 22 [PMID: 30457869] & compound 13c [PMID: 30457869]
3259	3.6.4.12 RecQ helicases family	WRN	WRN RecQ like helicase	Novel inhibitors curated with quantitative interaction data, including one (HRO761) in clinical development for oncology potential
3260	3.6.4.12 RecQ helicases family	BLM	BLM RecQ like helicase	Novel inhibitors curated with quantitative interaction data, including one allosteric inhibitor (compound 2 [PMID: 33647232])
3261	Coronavirus (CoV) proteins	ORF1ab	CoV nsp13 (helicase)	Novel inhibitors curated; antiviral potential- more details below
3262	E3 ubiquitin ligase components	KLHDC2	kelch domain containing 2	A substrate-recognition component of an E3 ligase complex that’s involved in the C-end degron protein homeostasis pathway; a tractable target for PROTAC design and development. A KLHDC2-based kinase degrading PROTAC (KYH1872) has been curated, which demonstrates the utility of exploiting KLHDC2 for targeted protein degradation in drug design.

Ligands

Since our last update in August 2023, the FDA have approved 20 new drugs (58 in total so far for 2023, so ahead of the 52 for all of 2022). Only 3 of these did not meet the criteria to be included in GtoPdb

20 newly approved drugs, 17 added to the GtoPdb
Ligand ID	INN	Trade name	Type	FDA Approval date	Indication	Other Approval date
12240	talquetamab-tgvs	Talvey	monoclonal antibody	09/08/2023	To treat adults with relapsed or refractory multiple myeloma who have received at least four prior therapies	n/a
12889	elranatamab-bcmm	Elrexfio	monoclonal antibody	14/08/2023	To treat adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy	n/a
8276	palovarotene	Sohonos	small molecule	16/08/2023	To reduce the volume of new heterotopic ossification in adults and pediatric patients (aged 8 years and older for females and 10 years and older for males) with fibrodysplasia ossificans progressiva	n/a
12900	pozelimab-bbfg	Veopoz	monoclonal antibody	18/08/2023	To treat patients 1 year old and older with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease	n/a
10679	motixafortide	Aphexda	peptide	08/09/2023	To use with filgrastim (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma	n/a
7791	momelotinib	Ojjaara	small molecule	15/09/2023	To treat intermediate or high-risk myelofibrosis in adults with anemia	n/a
12930	gepirone	Exxua	small molecule	22/09/2023	To treat major depressive disorder	n/a
n/a	cipaglucosidase alfa-atga	Pombiliti	peptide	28/09/2023	To treat late-onset Pompe disease	20/03/2023
n/a	nedosiran	Rivfloza	nucleotide	29/09/2023	To lower urinary oxalate levels in patients 9 years and older with primary hyperoxaluria type 1 and relatively preserved kidney function	n/a
9331	etrasimod	Velsipity	small molecule	12/10/2023	To treat moderately to severely active ulcerative colitis in adults	n/a
10404	zilucoplan	Zilbrysq	peptide	17/10/2023	To treat generalized myasthenia gravis in adults who are anti-acetylcholine receptor (AChR) antibody positive	n/a
9247	vamorolone	Agamree	small molecule	26/10/2023	To treat Duchenne muscular dystrophy	n/a
9846	mirikizumab-mrkz	Omvoh	monoclonal antibody	26/10/2023	To treat ulcerative colitis	26/05/2023
12989	toripalimab-tpzi	Loqtorzi	monoclonal antibody	30/10/2023	To treat advanced nasopharyngeal carcinoma	n/a
9428	fruquintinib	Fruzaqla	small molecule	09/11/2023	To treat metastatic colorectal cancer.	n/a
n/a	ADAMTS13, recombinant-krhn	Adzynma	peptide	09/11/2023	To treat congenital thrombotic thrombocytopenic purpura	n/a
10316	repotrectinib	Augtyro	small molecule	15/11/2023	To treat locally advanced or metastatic ROS1-positive non-small cell lung cancer	n/a
13030; 4214	taurolidine, heparin	Defencath	mixture	15/11/2023	To reduce the incidence of catheter-related bloodstream infections in adults with kidney failure receiving chronic hemodialysis through a central venous catheter	n/a
7709	capivasertib	Truqap	small molecule	16/11/2023	To treat HR+ve, HER2-ve adv breast cancer with AKT pathway activating mutations	n/a
7746	nirogacestat	Ogsiveo	small molecule	27/11/2023	To treat progressing desmoid tumours	n/a

SARS-CoV-2 & COVID-19

We have been keeping up to date with the progress of SARS-CoV-2 antiviral development by the COVID Moonshot open science project. In collaboration with the non-profit Drugs for Neglected Diseases initiative a clinical lead, DNDi-6510, has been selected, although its chemical structure has not yet been disclosed. We have however included a selection of Moonshot-discovered Mpro inhibitors as examples of their endeavours, and more details are available in the 2023 publication PMID: 37943932

The Moonshot Mpro inhibitors in GtoPdb are:

On the theme of SARS-CoV-2 antiviral development, we have included some new ligands that are reported as inhibitors of the CoV helicase (nsp13). Since the helicase is a crucial component of the CoV replication machinery, its inhibition is predicted to offer antiviral potential. Nsp13 is also reported to reduce the host interferon response, so limiting this effect would also likely contribute to COVID-19 therapeutic efficacy. To enhance nsp13’s inclusion we generated a new target entry (nsp13), to permit curation of quantitative ligand-target interaction data in the format used throughout other sections of the GtoPdb.

Nsp13 modulators curated are:

compound 16 [PMID: 31955138]

compound 4b [Ramsey et al., 2023]

compound 1b [PMID: 37562607]

Antibacterial Curation

Our collaboration with Antibiotic DB (ADB; www.antibioticdb.com) continues to allow us to extend the coverage of ligands with annotated antibacterial activity in GtoPdb and provide comprehensive chemistry and pharmacology for select antibacterials curated within ADB, via reciprocal links. This project is supported by the Global Antibiotic Research and Development Partnership (GARDP; https://gardp.org/).

Currently we have 507 ligands tagged in GtoPdb as ‘antibacterial’ and 488 of these have links to compounds at ADB. Since our last release we have added 35 new antibacterial ligands including:

19 drugs that are approved, or have been approved in the past, for clinical use in human
2 drugs that are approved for use in veterinary practice
2 that are WHO EML listed medicines
11 compounds that are in clinical development

Posted in Chemical curation, Database updates, Technical

One comment on “Database Release 2023.3”

Sarthak Roy says:

December 15, 2023 at 10:21 am

It’s a really very informative article are you share with us .It will very helpful
Thanks for sharing this type of informative content Keep sharing

Reply