Article
Author: Bar-David, Elad ; Lee, Alpha A. ; Fate, Gwen ; Fernandes, Rafaela S. ; Pšenák, Vladimír ; Sittner, Assa ; Saar, Kadi ; Noske, Gabriela D. ; Reddi, Rambabu N. ; Shurrush, Khriesto ; Hurley, Matthew F. D. ; Robinson, Ralph P. ; Alonzi, Dominic S. ; Aschenbrenner, Jasmin C. ; Solmesky, Leonardo J. ; Witt, Karolina D. ; Tumber, Anthony ; Tamir, Hadas ; Bennett, James ; Koekemoer, Lizbé ; Fraisse, Laurent ; Jnoff, Eric ; Kiappes, J. L. ; Singh, Sukrit ; Vaschetto, Mariana ; Dudgeon, Tim ; Mowbray, Charles E. ; Smalley, Adam ; Kovar, Boris ; Oliva, Glaucius ; Schiffer, Celia A. ; Marples, Peter G. ; Achdout, Hagit ; Melnykov, Kostiantyn P. ; Puni, Reut ; Borden, Bruce ; La, Van Ngoc Thuy ; Morris, Garrett M. ; Rufa, Dominic A. ; Bowman, Gregory R. ; Griffen, Ed J. ; Jochmans, Dirk ; Nakamura, Aline M. ; Shaikh, Aarif ; Varghese, Finny S. ; Pinjari, Jakir ; Shafeev, Mikhail ; Smilova, Mihaela D. ; García-Sastre, Adolfo ; Strain-Damerell, Claire ; Godoy, Andre S. ; Yahalom-Ronen, Yfat ; Chang, Edcon ; Milne, Bruce F. ; Rodriguez-Guerra, Jaime ; Gorrie-Stone, Tyler ; Robinson, Matthew C. ; Eastman, Peter ; Ben-Shmuel, Amir ; Vangeel, Laura ; Fedorov, Oleg ; Horrell, Sam ; Foster, Richard ; Weatherall, Charlie ; Owen, C. David ; Wild, Conor Francis ; Volkamer, Andrea ; Zhang, Ivy ; Schofield, Christopher J. ; Haneef, Amna ; Skyner, Rachael ; Gorichko, Marian ; De Jonghe, Steven ; Cole, Jason C. ; Powell, Ailsa ; Resnick, Efrat ; Gileadi, Carina ; Hassell Hart, Storm ; Macdonald, Hannah Bruce ; MacLean, Elizabeth M. ; Giroud, Charline ; Swamy, Vishwanath ; Duberstein, Shirly ; Pingle, Maneesh ; Glinert, Itai ; Kang, Lulu ; Bilenko, Vitaliy A. ; BVNBS, Sarma ; Wright, Nathan ; Spencer, John ; Smeets, Bart ; Schaller, David ; Reid, St Patrick ; Chodera, John D. ; Kaminow, Benjamin ; Gehrtz, Paul ; Neyts, Johan ; Brewitz, Lennart ; Henry, Michael ; Lefker, Bruce A. ; Carbery, Anna ; Ferla, Matteo ; Shaqra, Ala M. ; Foster, Holly ; Jajack, Andrew ; Cattermole, Emma ; Fairhead, Michael ; White, Kris M. ; Pai, Ruby ; Zvornicanin, Sarah N. ; McGovern, Briana L. ; Barr, Haim ; Sjö, Peter ; Huliak, Victor D. ; Gawriljuk, Victor O. ; Balcomb, Blake H. ; Heer, Jag ; von Delft, Frank ; Contini, Alessandro ; Kinakh, Serhii O. ; Weiss, Shay ; John, Tobias ; Tomásio, Susana ; Melamed, Sharon ; Tennant, Rachael E. ; Reid, Lauren ; Eyermann, Charles J. ; Boby, Melissa L. ; Pulido, Iván ; Glen, Robert C. ; Nguyen, Luong ; Cohen, Galit ; Miesen, Pascal ; Lithgo, Ryan M. ; Gabizon, Ronen ; Fearon, Daren ; Croll, Tristan Ian ; Payne, Alexander Matthew ; Kantsadi, Anastassia L. ; Paran, Nir ; Ripka, Emily Grace ; Yilmaz, Nese Kurt ; Voelz, Vincent ; Ward, Walter ; Hill, Michelle ; Tsurupa, Igor S. ; Arbon, Robert ; Donckers, Kim ; Erez, Noam ; Makower, Laetitia L. ; Zaidmann, Daniel ; Rosales, Romel ; Krojer, Tobias ; Chernyshenko, Eugene ; Israely, Tomer ; Ferrins, Lori ; Boulet, Pascale ; Matviiuk, Tatiana ; Kenny, Peter W. ; Tomlinson, Charles W. E. ; Cvitkovic, Milan ; Filep, Mihajlo ; von Delft, Annette ; Thompson, Andrew ; Zidane, Hadeer ; Calmiano, Mark ; Morris, Aaron ; Logvinenko, Ivan G. ; Carney, Daniel W. ; Cox, Lisa ; Vitner, Einat B. ; Douangamath, Alice ; Dunnett, Louise E. ; Mikolajek, Halina ; Lukacik, Petra ; Morwitzer, Melody Jane ; Laghnimi-Hahn, Sophie ; McCorkindale, Willam ; Thompson, Warren ; Moustakas, Demetri ; Levy, Haim ; Aimon, Anthony ; Huang, Qiu Yu Judy ; Clyde, Austin ; Vakonakis, Ioannis ; Wittmann, Matthew ; Neto, Jose Brandao ; Rangel, Victor L. ; Minh, David ; Overheul, Gijs J. ; Walsh, Martin A. ; Perry, Benjamin ; Shi, Jiye ; Rees, Paul ; Scheen, Jenke ; Michurin, Oleg ; Zitzmann, Nicole ; London, Nir ; Pan, Jin ; Coffland, Joseph E. ; Politi, Boaz ; Salah, Eidarus ; Taylor, Jenny C. ; Dotson, David L. ; van Rij, Ronald P. ; Brun, Juliane ; Saikatendu, Kumar Singh ; Jansen, Jitske ; Oleinikovas, Vladas ; Dias, Alex ; Glass, William G. ; Malla, Tika R.
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.