Curating SARS-CoV-2 viral targets for the IUPHAR/BPS Guide to Pharmacology
Christopher Southan · Zenodo (CERN European Organization for Nuclear Research) · 2020
Slides from oral presentation at BPS 2020 (recording available on request) Introduction. While SARS-CoV-2 vaccine development is progressing, it is crucial to pursue antiviral small-molecules in parallel because of a) probability of becoming endemic b) historical successes of HIV and Hepatis C antivirals c) possibility of wider inter-strain effectiveness and d) global collaborative consortia shortening development timelines. Consequent to a Wellcome Trust, grant the IUPHAR/BPS Guide to Pharmacology (GtoPdb) is now curating inhibitors for coronaviral targets [1] Methods. GtoPdb implements a long-established workflow for stringent expert curation of published quantitative ligand-target interactions [2]. Predictably, for COVID-19, the triage of quality papers and pre-prints from 85,000 published in 2020, is challenging and exacerbated by many inhibitor reports based solely on in-silico predictions. By setting potency thresholds we selected a small number of data-supported inhibition papers but in some cases resolving the molecular structures proves difficult. Results for viral replication inhibition have also been captured. . Social media and the Open Source COVID-19 research consortium are providing useful alerts for key papers. We also check new viral target PDB ligand entries for their PubChem connections to publications and patents. Results. We have mined earlier SARS-CoV-1 and MERS literature for medicinal chemistry results against targets with tractable assays such as the M- and PL-proteases. For SARS-CoV-2 we found homologues of these and now annotated target records for 12 SARS-CoV-2 proteins (see family ID 1034). As an example, the SARS-Cov-2 Main protease (Target id: 3111) has the most ligands so far including the older SARS reference compounds GC376 (ligand ID 10883) and N3 (ligand ID 10716). However, published potencies vary widely due to irreversible binding. Having annotated 21 distinct ligands with 28 interactions against 3 targets we continue to capture published inhibitors for other virally-encoded enzymes and antagonists of the Spike/ACE2 interaction. Conclusions The GtoPdb capture of small-molecule inhibitors provides an open and authoritative resource for SARS-CoV-2 targets valuable for widening experimental consolidation. Along with those for selected COVID-19-relevant human proteins [1] these annotations are now part of our Coronavirus Information portal (www.guidetopharmacology.org/GRAC/CoronavirusForward) and one of the BPS COVID-19 Research hub links. Our curation indicates slow progress towards new treatments as judged by the paucity of sub-uM inhibition results. However, as more data is published and various consortia move into high gear for screening we anticipate that a) low nM potencies may be achieved b) Artificial Intelligence (AI) approaches will accelerate optimisation and c) the cocktail approach so effective for HIV will become viable. References [1] Alexander SPH, Armstrong JF, Davenport AP, Davies JA, Faccenda E, Harding SD, Levi-Schaffer F, Maguire JJ, Pawson AJ, Southan C, and Spedding M. (2020) Br J Pharmacol. doi: 10.1111/bph.15094, PMID 32358833 [2] 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 (2020) Nucleic Acids Res. doi: 10.1093/nar/gkz951, PMID 31691834