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COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

By The COVID Moonshot Consortium, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L Bobby, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Emma Cattermole, John D. Chodera, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Alice Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, Peter K. Eastman, Noam Erez, Michael Fairhead, Daren Fearon, Oleg Fedorov, Matteo Ferla, Holly Foster, Richard Foster, Ronen Gabizon, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G. Glass, Robert Glen, Itai Glinert, Marian Gorichko, Tyler J Gorrie-Stone, Edward J Griffen, Jag Heer, Michelle L. Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Tobias John, Anastassia L. Kantsadi, Peter W. Kenny, J.L. Kiappes, Lizbe Koekemoer, Boris Kovar, Tobias Krojer, Alpha Albert Lee, Bruce A. Lefker, Haim Levy, Nir London, Petra Lukacik, Hannah Bruce Macdonald, Beth MacLean, Tika R Malla, Tatiana Matviiuk, Willam McCorkindale, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Aaron Morris, Garrett M. Morris, Melody Jane Morwitzer, Demetri Moustakas, Jose Brandao Neto, Vladas Oleinikovas, Gijs J. Overheul, David Owen, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa J Powell, Vladimir Psenak, Reut Puni, Victor L Rangel, Rambabu N. Reddi, St Patrick Reid, Efrat Resnick, Matthew C Robinson, Ralph P. Robinson, Dominic Rufa, Christopher J Schofield, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Assa Sittner, Rachael E Skyner, Adam Smalley, Mihaela D. Smilova, John Spencer, Claire Strain-Damerell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, Andrew Thompson, Warren Thompson, Susana Tomasio, Anthony Tumber, Ioannis Vakonakis, Ronald P. van Rij, Finny S. Varghese, Mariana Vaschetto, Einat. B. Vitner, Vincent Voelz, Annette von Delft, Frank von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Conor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, Nicole Zitzmann

Posted 30 Oct 2020
bioRxiv DOI: 10.1101/2020.10.29.339317

Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use. ### Competing Interest Statement The authors have declared no competing interest.

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