COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

The COVID Moonshot Consortium,; Achdout, H.; Aimon, A.; Bar-David, E.; Barr, H.; Ben-Shmuel, A.; Bennett, J.; Bobby, M. L.; Brun, J.; BVNBS, S.; Calmiano, M.; Carbery, A.; Cattermole, E.; Chodera, J. D.; Clyde, A.; Coffland, J. E.; Cohen, G.; Cole, J.; Contini, A.; Cox, L.; Cvitkovic, M.; Dias, A.; Douangamath, A.; Duberstein, S.; Dudgeon, T.; Dunnett, L.; Eastman, P. K.; Erez, N.; Fairhead, M.; Fearon, D.; Fedorov, O.; Ferla, M.; Foster, H.; Foster, R.; Gabizon, R.; Gehrtz, P.; Gileadi, C.; Giroud, C.; Glass, W. G.; Glen, R.; Glinert, I.; Gorichko, M.; Gorrie-Stone, T.; Griffen, E. J.; Heer

doi:10.1101/2020.10.29.339317

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bioRxiv · 10.1101/2020.10.29.339317

COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

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Abstract

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 non-covalent, non-peptidic 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 (>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.

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The COVID Moonshot Consortium,, Achdout, H., Aimon, A., Bar-David, E., Barr, H., Ben-Shmuel, A., Bennett, J., Bobby, M. L., Brun, J., BVNBS, S., Calmiano, M., Carbery, A., Cattermole, E., Chodera, J. D., Clyde, A., Coffland, J. E., Cohen, G., Cole, J., Contini, A., Cox, L., Cvitkovic, M., Dias, A., Douangamath, A., Duberstein, S., Dudgeon, T., Dunnett, L., Eastman, P. K., Erez, N., Fairhead, M., Fearon, D., Fedorov, O., Ferla, M., Foster, H., Foster, R., Gabizon, R., Gehrtz, P., Gileadi, C., Giroud, C., Glass, W. G., Glen, R., Glinert, I., Gorichko, M., Gorrie-Stone, T., Griffen, E. J., Heer. 2020-10-30. COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning. https://doi.org/10.1101/2020.10.29.339317

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