Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Authors: Boby Melissa L. , Fearon Daren , Ferla Matteo , Filep Mihajlo , Koekemoer Lizbé , Robinson Matthew C. ,   The COVID Moonshot Consortium‡, Chodera John D. , Lee Alpha A. , London Nir , von Delft Annette , von Delft Frank , Achdout Hagit , Aimon Anthony , Alonzi Dominic S. , Arbon Robert , Aschenbrenner Jasmin C. , Balcomb Blake H. , Bar-David Elad , Barr Haim , Ben-Shmuel Amir , Bennett James , Bilenko Vitaliy A. , Borden Bruce , Boulet Pascale , Bowman Gregory R. , Brewitz Lennart , Brun Juliane , BVNBS Sarma , Calmiano Mark , Carbery Anna , Carney Daniel W. , Cattermole Emma , Chang Edcon , Chernyshenko Eugene , Clyde Austin , Coffland Joseph E. , Cohen Galit , Cole Jason C. , Contini Alessandro , Cox Lisa , Croll Tristan Ian , Cvitkovic Milan , De Jonghe Steven , Dias Alex , Donckers Kim , Dotson David L. , Douangamath Alice , Duberstein Shirly , Dudgeon Tim , Dunnett Louise E. , Eastman Peter , Erez Noam , Eyermann Charles J. , Fairhead Michael , Fate Gwen , Fedorov Oleg , Fernandes Rafaela S. , Ferrins Lori , Foster Richard , Foster Holly , Fraisse Laurent , Gabizon Ronen , García-Sastre Adolfo , Gawriljuk Victor O. , Gehrtz Paul , Gileadi Carina , Giroud Charline , Glass William G. , Glen Robert C. , Glinert Itai , Godoy Andre S. , Gorichko Marian , Gorrie-Stone Tyler , Griffen Ed J. , Haneef Amna , Hassell Hart Storm , Heer Jag , Henry Michael , Hill Michelle , Horrell Sam , Huang Qiu Yu Judy , Huliak Victor D. , Hurley Matthew F. D. , Israely Tomer , Jajack Andrew , Jansen Jitske , Jnoff Eric , Jochmans Dirk , John Tobias , Kaminow Benjamin , Kang Lulu , Kantsadi Anastassia L. , Kenny Peter W. , Kiappes J. L. , Kinakh Serhii O. , Kovar Boris , Krojer Tobias , La Van Ngoc Thuy , Laghnimi-Hahn Sophie , Lefker Bruce A. , Levy Haim , Lithgo Ryan M. , Logvinenko Ivan G. , Lukacik Petra , Macdonald Hannah Bruce , MacLean Elizabeth M. , Makower Laetitia L. , Malla Tika R. , Marples Peter G. , Matviiuk Tatiana , McCorkindale Willam , McGovern Briana L. , Melamed Sharon , Melnykov Kostiantyn P. , Michurin Oleg , Miesen Pascal , Mikolajek Halina , Milne Bruce F. , Minh David , Morris Aaron , Morris Garrett M. , Morwitzer Melody Jane , Moustakas Demetri , Mowbray Charles E. , Nakamura Aline M. , Neto Jose Brandao , Neyts Johan , Nguyen Luong , Noske Gabriela D. , Oleinikovas Vladas , Oliva Glaucius , Overheul Gijs J. , Owen C. David , Pai Ruby , Pan Jin , Paran Nir , Payne Alexander Matthew , Perry Benjamin , Pingle Maneesh , Pinjari Jakir , Politi Boaz , Powell Ailsa , Pšenák Vladimír , Pulido Iván , Puni Reut , Rangel Victor L. , Reddi Rambabu N. , Rees Paul , Reid St Patrick , Reid Lauren , Resnick Efrat , Ripka Emily Grace , Robinson Ralph P. , Rodriguez-Guerra Jaime , Rosales Romel , Rufa Dominic A. , Saar Kadi , Saikatendu Kumar Singh , Salah Eidarus , Schaller David , Scheen Jenke , Schiffer Celia A. , Schofield Christopher J. , Shafeev Mikhail , Shaikh Aarif , Shaqra Ala M. , Shi Jiye , Shurrush Khriesto , Singh Sukrit , Sittner Assa , Sjö Peter , Skyner Rachael , Smalley Adam , Smeets Bart , Smilova Mihaela D. , Solmesky Leonardo J. , Spencer John , Strain-Damerell Claire , Swamy Vishwanath , Tamir Hadas , Taylor Jenny C. , Tennant Rachael E. , Thompson Warren , Thompson Andrew , Tomásio Susana , Tomlinson Charles W. E. , Tsurupa Igor S. , Tumber Anthony , Vakonakis Ioannis , van Rij Ronald P. , Vangeel Laura , Varghese Finny S. , Vaschetto Mariana , Vitner Einat B. , Voelz Vincent , Volkamer Andrea , Walsh Martin A. , Ward Walter , Weatherall Charlie , Weiss Shay , White Kris M. , Wild Conor Francis , Witt Karolina D. , Wittmann Matthew , Wright Nathan , Yahalom-Ronen Yfat , Yilmaz Nese Kurt , Zaidmann Daniel , Zhang Ivy , Zidane Hadeer , Zitzmann Nicole , Zvornicanin Sarah N. 
Published: November 2023

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.