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- The COVID Moonshot Initiative; Hagit Achdout; Anthony Aimon; Elad Bar-David; Haim Barr; Amir Ben-Shmuel; James Bennett; Vitaliy A. Bilenko; Vitaliy A. Bilenko; Melissa L. Boby; Bruce Borden; Gregory R. Bowman; Juliane Brun; Sarma BVNBS; Mark Calmiano; Anna Carbery; Daniel Carney; Emma Cattermole; Edcon Chang; Eugene Chernyshenko; John D. Chodera; Austin Clyde; Joseph E. Coffland; Galit Cohen; Jason Cole; Alessandro Contini; Lisa Cox; Milan Cvitkovic; Alex Dias; Kim Donckers; David L. Dotson; Alice Douangamath; Shirly Duberstein; Tim Dudgeon; Louise Dunnett; Peter K. Eastman; Noam Erez; Charles J. Eyermann; Mike Fairhead; Gwen Fate; Daren Fearon; Oleg Fedorov; Matteo Ferla; Rafaela S. Fernandes; Lori Ferrins; Richard Foster; Holly Foster; Ronen Gabizon; Adolfo Garcia-Sastre; Victor O. Gawriljuk; Paul Gehrtz; Carina Gileadi; Charline Giroud; William G. Glass; Robert Glen; Itai Glinert; Andre S. Godoy; Marian Gorichko; Tyler Gorrie-Stone; Ed J. Griffen; Storm Hassell Hart; Jag Heer; Michael Henry; Michelle Hill; Sam Horrell; Victor D. Huliak; Matthew F.D. Hurley; Tomer Israely; Andrew Jajack; Jitske Jansen; Eric Jnoff; Dirk Jochmans; Tobias John; Steven De Jonghe; Anastassia L. Kantsadi; Peter W. Kenny; J. L. Kiappes; Serhii O. Kinakh; Lizbe Koekemoer; Boris Kovar; Tobias Krojer; Alpha Lee; Bruce A. Lefker; Haim Levy; Ivan G. Logvinenko; Nir London; Petra Lukacik; Hannah Bruce Macdonald; Beth MacLean; Tika R. Malla; Tatiana Matviiuk; Willam McCorkindale; Briana L. McGovern; Sharon Melamed; Kostiantyn P. Melnykov; Oleg Michurin; Halina Mikolajek; Bruce F. Milne; Aaron Morris; Garrett M. Morris; Melody Jane Morwitzer; Demetri Moustakas; Aline M. Nakamura; Jose Brandao Neto; Johan Neyts; Luong Nguyen; Gabriela D. Noske; Vladas Oleinikovas; Glaucius Oliva; Gijs J. Overheul; David Owen; Ruby Pai; Jin Pan; Nir Paran; Benjamin Perry; Maneesh Pingle; Jakir Pinjari; Boaz Politi; Ailsa Powell; Vladimir Psenak; Reut Puni; Victor L. Rangel; Rambabu N. Reddi; St Patrick Reid; Efrat Resnick; Emily Grace Ripka; Matthew C. Robinson; Ralph P. Robinson; Jaime Rodriguez-Guerra; Romel Rosales; Dominic Rufa; Kadi Saar; Kumar Singh Saikatendu; Chris Schofield; Mikhail Shafeev; Aarif Shaikh; Jiye Shi; Khriesto Shurrush; Sukrit Singh; Assa Sittner; Rachael Skyner; Adam Smalley; Bart Smeets; Mihaela D. Smilova; Leonardo J. Solmesky; John Spencer; Claire Strain-Damerell; Vishwanath Swamy; Hadas Tamir; Rachael Tennant; Warren Thompson; Andrew Thompson; Susana Tomasio; 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; Frank von Delft; Annette von Delft; Martin Walsh; Walter Ward; Charlie Weatherall; Shay Weiss; Kris M. White; Conor Francis Wild; Matthew Wittmann; Nathan Wright; Yfat Yahalom-Ronen; Daniel Zaidmann; Hadeer Zidane; Nicole Zitzmann.
Preprint in English | PREPRINT-BIORXIV | ID: ppbiorxiv-339317

ABSTRACT

The COVID-19 pandemic is a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, easily deployable broad-spectrum oral antivirals and open knowledge bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results of the COVID Moonshot, a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical scaffold that is differentiated from current clinical candidates in terms of toxicity, resistance, and pharmacokinetics liabilities, and developed it into noncovalent orally-bioavailable nanomolar inhibitors with clinical potential. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations. In the process, we generated a detailed map of the structural plasticity of the main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

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