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