Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

• DOI: 10.1126/science.abo7201
• Publication Date: 2023-11-09T18:59:31Z
• Authors: Melissa L. Boby; Daren Fearon; Matteo Ferla; Mihajlo Filep; Lizbé Koekemoer; Matthew C. Robinson; ; John D. Chodera; Alpha A. Lee; Nir London; Annette von Delft; Frank von Delft; Hagit Achdout; Anthony Aimon; Dominic S. Alonzi; Robert Arbon; Jasmin C. Aschenb...; Blake H. Balcomb; Elad Bar-David; Haim Barr; Amir Ben-Shmuel; James 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 Cox; Tristan Ian Croll; Milan Cvitkovic; Steven De Jonghe; Alex Dias; Kim Donckers; David L. Dotson; Alice Douangamath; Shirly Duberstein; Tim Dudgeon; Louise E. Dunnett; Peter Eastman; Noam Erez; Charles J. Eyermann; Michael Fairhead; Gwen Fate; Oleg Fedorov; Rafaela S. Fernandes; Lori Ferrins; Richard Foster; Holly Foster; Laurent Fraisse; Ronen Gabizon; Adolfo García-Sastre; Victor O. Gawriljuk; Paul Gehrtz; Carina Gileadi; Charline Giroud; William G. Glass; Robert C. Glen; Itai Glinert; Andre S. Godoy; Marian Gorichko; Tyler Gorrie-Stone; Ed J. Griffen; Amna Haneef; Storm Hassell Hart; Jag Heer; Michael Henry; Michelle Hill; Sam Horrell; Qiu Yu Judy Huang; Victor D. Huliak; Matthew F. D. Hurley; Tomer Israely; Andrew Jajack; Jitske Jansen; Eric Jnoff; Dirk Jochmans; Tobias John; Benjamin Kaminow; Lulu Kang; Anastassia L. Kan...; Peter W. Kenny; J. L. Kiappes; Serhii O. Kinakh; Boris Kovar; Tobias Krojer; Van Ngoc Thuy La; Sophie Laghnimi-Hahn; Bruce A. Lefker; Haim Levy; Ryan M. Lithgo; Ivan G. Logvinenko; Petra Lukacik; Hannah Bruce Macd...; Elizabeth M. MacLean; Laetitia L. Makower; Tika R. Malla; Peter G. Marples; Tatiana Matviiuk; Willam McCorkindale; Briana L. McGovern; Sharon Melamed; Kostiantyn P. Mel...; Oleg Michurin; Pascal Miesen; Halina Mikolajek; Bruce F. Milne; David Minh; Aaron Morris; Garrett M. Morris; Melody Jane Morwi...; Demetri Moustakas; Charles E. Mowbray; Aline M. Nakamura; Jose Brandao Neto; Johan Neyts; Luong Nguyen; Gabriela D. Noske; Vladas Oleinikovas; Glaucius Oliva; Gijs J. Overheul; C. David Owen; Ruby Pai; Jin Pan; Nir Paran; Alexander Matthew...; Benjamin Perry; Maneesh Pingle; Jakir Pinjari; Boaz Politi; Ailsa Powell; Vladimír Pšenák; Iván Pulido; Reut Puni; Victor L. Rangel; Rambabu N. Reddi; Paul Rees; St Patrick Reid; Lauren Reid; Efrat Resnick; Emily Grace Ripka; Ralph P. Robinson; Jaime Rodriguez-G...; Romel Rosales; Dominic A. Rufa; Kadi Saar; Kumar Singh Saika...; Eidarus Salah; David Schaller; Jenke Scheen; Celia A. Schiffer; Christopher J. Sc...; Mikhail Shafeev; Aarif Shaikh; Ala M. Shaqra; Jiye Shi; Khriesto Shurrush; Sukrit Singh; Assa Sittner; Peter Sjö; Rachael Skyner; Adam Smalley; Bart Smeets; Mihaela D. Smilova; Leonardo J. Solmesky; John Spencer; Claire Strain-Dam...; Vishwanath Swamy; Hadas Tamir; Jenny C. Taylor; Rachael E. Tennant; Warren Thompson; Andrew Thompson; Susana Tomásio; Charles W. E. Tom...; Igor S. Tsurupa; Anthony Tumber; Ioannis Vakonakis; Ronald P. van Rij; Laura Vangeel; Finny S. Varghese; Mariana Vaschetto; Einat B. Vitner; Vincent Voelz; Andrea Volkamer; Martin A. Walsh; Walter Ward; Charlie Weatherall; Shay Weiss; Kris M. White; Conor Francis Wild; Karolina D. Witt; Matthew Wittmann; Nathan Wright; Yfat Yahalom-Ronen; Nese Kurt Yilmaz; Daniel Zaidmann; Ivy Zhang; Hadeer Zidane; Nicole Zitzmann; Sarah N. Zvornicanin
• Keywords: 0301 basic medicine; SARS-CoV-2; mPro; Open Science; Drug Discovery; COVID-19; SARS-CoV-2; Radboud University Medical Center; Crystallography, X-Ray; Radboudumc 4: lnfectious Diseases and Global Health Medical Microbiology; Article; COVID-19 Drug Treatment; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Coronavirus Protease Inhibitors; Drug Discovery; Humans; Radboudumc 11: Renal disorders Pathology; Coronavirus 3C Proteases

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.