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bioRxiv Preprint

The COVID-19 pandemic was a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Pandemics could be prevented in principle by accessible, easily deployable broad-spectrum oral antivirals. Here we report the results of the COVID Moonshot, a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical series that is differentiated from current Mpro inhibitors in that it maintains a new non-covalent, non-peptidic scaffold with nanomolar potency. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations and high-throughput chemistry. In the process, 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. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

The COVID Moonshot Consortium, ; Achdout, H.; Aimon, A.; Alonzi, D. S.; Arbon, R.; Bar-David, E.; Barr, H.; Ben-Shmuel, A.; Bennett, J.; Bilenko, V. A.; Bilenko, V. A.; Boby, M. L.; Borden, B.; Boulet, P.; Bowman, G. R.; Brun, J.; Brwewitz, L.; BVNBS, S.; Calmiano, M.; Carbery, A.; Carney, D.; Cattermole, E.; Chang, E.; Chernyshenko, E.; Chodera, J. D.; Clyde, A.; Coffland, J. E.; Cohen, G.; Cole, J.; Contini, A.; Cox, L.; Croll, T. I.; Cvitkovic, M.; Dias, A.; Donckers, K.; Dotson, D. L.; Douangamath, A.; Duberstein, S.; Dudgeon, T.; Dunnett, L.; Eastman, P. K.; Erez, N.; Eyermann, C. J.; Fa