Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors Journal Article
| Authors: | Boby, M. L.; Fearon, D.; Ferla, M.; Filep, M.; Koekemoer, L.; Robinson, M. C.; The COVID Moonshot Consortium; Chodera, J. D.; Lee, A. A.; London, N.; von Delft, A. |
| Contributors: | Arbon, R.; Glass, W.; Henry, M.; Kaminow, B.; Bruce Macdonald, H.; Payne, A. M.; Pulido, I.; Rufa, D. A.; Scheen, J.; Singh, S.; Wittmann, M.; Zhang, I. |
| Article Title: | Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors |
| Abstract: | We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery. |
| Keywords: | protease inhibitors; chemistry; antivirus agent; molecular docking; proteinase inhibitor; antiviral agents; humans; human; molecular docking simulation; severe acute respiratory syndrome coronavirus 2; coronavirus disease 2019; covid-19; sars-cov-2; coronavirus 3c proteases; 3c-like proteinase, sars-cov-2; coronavirus 3c protease |
| Journal Title: | Science |
| Volume: | 382 |
| Issue: | 6671 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2023-11-10 |
| Start Page: | eabo7201 |
| Language: | English |
| DOI: | 10.1126/science.abo7201 |
| PUBMED: | 37943932 |
| PROVIDER: | scopus |
| PMCID: | PMC7615835 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF Supplement (data table S7) Source: Scopus |
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