Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Melissa L. Boby, D. Fearon, Matteo P. Ferla, Mihajlo Filep, L. Koekemoer, Matthew C. Robinson, John D. Chodera, Alpha A. Lee, Nir London, Annette von Delft, F. von Delft, Hagit Achdout, A. Aimon, Dominic S. Alonzi, Robert Arbon, J.C. Aschenbrenner, Blake Balcomb, Elad Bar-David, Haim Barr, Amir Ben‐Shmuel, James M. Bennett, Vitaliy A. Bilenko, Bruce Borden, Pascale Boulet, Gregory R. Bowman, Lennart Brewitz, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Daniel W. Carney, Emma Cattermole, Edcon Chang, Eugene Chernyshenko, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason C. Cole, Alessandro Contini, Lisa Sanderson Cox, Tristan I. Croll, Milan Cvitkovic, Steven De Jonghe, Alex Dias, Kim Donckers, David Dotson, A. Douangamath, Shirly Duberstein, Tim Dudgeon, Louise E. Dunnett, Peter Eastman, Noam Erez, Charles J. Eyermann, M. Fairhead, Gwen Fate, O. Fedorov, R.S. Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Laurent Fraisse, Ronen Gabizon, Adolfo García‐Sastre, Victor O. Gawriljuk, Paul Gehrtz, C. Gileadi, Charline Giroud, William G. Glass, Robert C. Glen, Itai Glinert, André S. Godoy, Marian V. Gorichko, T.J. Gorrie-Stone, Ed Griffen, Amna Haneef, Storm Hassell Hart, Jag Heer, Michael M. Henry, Michelle L. Hill, Sam Horrell, Qiu Yu J. Huang, Victor D. Huliak, Matthew F. D. Hurley, Tomer Israely, Andrew J. Jajack, Jitske Jansen, Eric Jnoff, Dirk Jochmans, Tobias John, Benjamin Kaminow, Lulu Kang, A.L. Kantsadi, Peter W. Kenny, J. L. Kiappes, Serhii O. Kinakh, Boris Kovar, T. Krojer, Van Ngoc Thuy La, Sophie Laghnimi-Hahn, Bruce A. Lefker
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.