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.
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.
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.
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-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|
- 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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