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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

The COVID Moonshot Consortium, Hagit Achdout, View ORCID ProfileAnthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, View ORCID ProfileMelissa L Bobby, View ORCID ProfileJuliane Brun, BVNBS Sarma, Mark Calmiano, Anna Carbery, Emma Cattermole, View ORCID ProfileJohn D. Chodera, Austin Clyde, View ORCID ProfileJoseph E. Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Alice Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, View ORCID ProfilePeter K. Eastman, Noam Erez, View ORCID ProfileMichael Fairhead, View ORCID ProfileDaren Fearon, Oleg Fedorov, Matteo Ferla, Holly Foster, Richard Foster, Ronen Gabizon, Paul Gehrtz, Carina Gileadi, Charline Giroud, View ORCID ProfileWilliam G. Glass, Robert Glen, Itai Glinert, Marian Gorichko, View ORCID ProfileTyler Gorrie-Stone, View ORCID ProfileEdward J Griffen, Jag Heer, View ORCID ProfileMichelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Tobias John, Anastassia L. Kantsadi, View ORCID ProfilePeter W. Kenny, View ORCID ProfileJohn L. Kiappes, View ORCID ProfileLizbe Koekemoer, Boris Kovar, View ORCID ProfileTobias Krojer, View ORCID ProfileAlpha Albert Lee, View ORCID ProfileBruce A. Lefker, Haim Levy, View ORCID ProfileNir London, Petra Lukacik, View ORCID ProfileHannah Bruce Macdonald, Beth MacLean, View ORCID ProfileTika R. Malla, Tatiana Matviiuk, Willam McCorkindale, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Aaron Morris, View ORCID ProfileGarrett M. Morris, Melody Jane Morwitzer, Demetri Moustakas, View ORCID ProfileJose Brandao Neto, View ORCID ProfileVladas Oleinikovas, View ORCID ProfileGijs J. Overheul, David Owen, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, View ORCID ProfileAilsa Powell, Vladimir Psenak, Reut Puni, View ORCID ProfileVictor L. Rangel, Rambabu N. Reddi, St Patrick Reid, Efrat Resnick, Matthew C. Robinson, Ralph P. Robinson, View ORCID ProfileDominic Rufa, View ORCID ProfileChristopher Schofield, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Assa Sittner, Rachael Skyner, Adam Smalley, View ORCID ProfileMihaela D. Smilova, View ORCID ProfileJohn Spencer, Claire Strain-Damerell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, View ORCID ProfileAndrew Thompson, View ORCID ProfileWarren Thompson, Susana Tomasio, Anthony Tumber, View ORCID ProfileIoannis Vakonakis, View ORCID ProfileRonald P. van Rij, View ORCID ProfileFinny S. Varghese, Mariana Vaschetto, Einat B. Vitner, Vincent Voelz, View ORCID ProfileAnnette von Delft, View ORCID ProfileFrank von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, View ORCID ProfileConor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, View ORCID ProfileNicole Zitzmann
doi: https://doi.org/10.1101/2020.10.29.339317
1Israel Institute for Biological Research
Hagit Achdout
1Israel Institute for Biological Research
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Anthony Aimon
2Diamond Light Source Ltd; Research Complex at Harwell
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Elad Bar-David
1Israel Institute for Biological Research
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Haim Barr
3The Weizmann Institute of Science
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Amir Ben-Shmuel
1Israel Institute for Biological Research
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James Bennett
4University of Oxford
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Melissa L Bobby
5Memorial Sloan Kettering Cancer Center;Weil Cornell Medical College
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Juliane Brun
4University of Oxford
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BVNBS Sarma
6Sai Life Sciences
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Mark Calmiano
7UCB
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Anna Carbery
8University of Oxford;Diamond Light Source
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Emma Cattermole
4University of Oxford
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John D. Chodera
9Memorial Sloan Kettering Cancer Center
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Austin Clyde
10Argonne National Laboratory
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Joseph E. Coffland
11Couldron Development
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Galit Cohen
3The Weizmann Institute of Science
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Jason Cole
12Cambridge Crystallographic Data Centre
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Alessandro Contini
13University of Milan
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Lisa Cox
14Life Compass Consulting Ltd
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Milan Cvitkovic
15PostEra Inc.
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Alex Dias
2Diamond Light Source Ltd; Research Complex at Harwell
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Alice Douangamath
2Diamond Light Source Ltd; Research Complex at Harwell
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Shirly Duberstein
3The Weizmann Institute of Science
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Tim Dudgeon
16Informatics Matters
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Louise Dunnett
2Diamond Light Source Ltd; Research Complex at Harwell
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Peter K. Eastman
17Department of Bioengineering until Sept. 1, then Department of Chemistry
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Noam Erez
1Israel Institute for Biological Research
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Michael Fairhead
4University of Oxford
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Daren Fearon
2Diamond Light Source Ltd; Research Complex at Harwell
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Oleg Fedorov
4University of Oxford
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Matteo Ferla
4University of Oxford
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Holly Foster
18University of Leeds
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Richard Foster
18University of Leeds
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Ronen Gabizon
3The Weizmann Institute of Science
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Paul Gehrtz
3The Weizmann Institute of Science
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Carina Gileadi
4University of Oxford
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Charline Giroud
4University of Oxford
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William G. Glass
9Memorial Sloan Kettering Cancer Center
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Robert Glen
19University of Cambridge
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Itai Glinert
1Israel Institute for Biological Research
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Marian Gorichko
20Taras Shevchenko National University of Kyiv
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Tyler Gorrie-Stone
2Diamond Light Source Ltd; Research Complex at Harwell
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Edward J Griffen
21MedChemica Ltd
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Jag Heer
7UCB
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Michelle Hill
4University of Oxford
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Sam Horrell
2Diamond Light Source Ltd; Research Complex at Harwell
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Matthew F.D. Hurley
22Temple University
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Tomer Israely
1Israel Institute for Biological Research
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Andrew Jajack
15PostEra Inc.
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Eric Jnoff
7UCB
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Tobias John
4University of Oxford
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Anastassia L. Kantsadi
4University of Oxford
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Peter W. Kenny
23Universidade de Sao Paulo
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John L. Kiappes
4University of Oxford
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Lizbe Koekemoer
4University of Oxford
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Boris Kovar
24M2M solutions, s.r.o
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Tobias Krojer
4University of Oxford
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Alpha Albert Lee
19University of Cambridge
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  • For correspondence: john.chodera@choderalab.org alpha.lee@postera.ai nir.london@weizmann.ac.il frank.von-delft@diamond.ac.uk
Bruce A. Lefker
25Thames Pharma Partners LLC
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Haim Levy
1Israel Institute for Biological Research
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Nir London
3The Weizmann Institute of Science
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Petra Lukacik
2Diamond Light Source Ltd; Research Complex at Harwell
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Hannah Bruce Macdonald
9Memorial Sloan Kettering Cancer Center
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Beth MacLean
4University of Oxford
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Tika R. Malla
4University of Oxford
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Tatiana Matviiuk
26Enamine Ltd
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Willam McCorkindale
19University of Cambridge
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Sharon Melamed
1Israel Institute for Biological Research
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Oleg Michurin
26Enamine Ltd
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2Diamond Light Source Ltd; Research Complex at Harwell
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Aaron Morris
27PostEra Inc
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Garrett M. Morris
4University of Oxford
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Melody Jane Morwitzer
28University of Nebraska at Kearney
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Demetri Moustakas
29Relay Therapeutics
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Jose Brandao Neto
2Diamond Light Source Ltd; Research Complex at Harwell
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Vladas Oleinikovas
7UCB
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Gijs J. Overheul
30Radboud University Medical Center
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David Owen
2Diamond Light Source Ltd; Research Complex at Harwell
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15PostEra Inc.
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Jin Pan
15PostEra Inc.
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Nir Paran
1Israel Institute for Biological Research
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31DNDi
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6Sai Life Sciences
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6Sai Life Sciences
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Boaz Politi
32Israel Institute of Biological Research
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2Diamond Light Source Ltd; Research Complex at Harwell
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Vladimir Psenak
24M2M solutions, s.r.o
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Reut Puni
32Israel Institute of Biological Research
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Victor L. Rangel
33School of Pharmaceutical Sciences of Ribeirao Preto
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Rambabu N. Reddi
3The Weizmann Institute of Science
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34University of Nebraska
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3The Weizmann Institute of Science
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15PostEra Inc.
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25Thames Pharma Partners LLC
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9Memorial Sloan Kettering Cancer Center
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4University of Oxford
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6Sai Life Sciences
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7UCB
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Khriesto Shurrush
3The Weizmann Institute of Science
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Assa Sittner
32Israel Institute of Biological Research
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2Diamond Light Source Ltd; Research Complex at Harwell
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7UCB
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4University of Oxford
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John Spencer
35University of Sussex
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Claire Strain-Damerell
2Diamond Light Source Ltd; Research Complex at Harwell
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Vishwanath Swamy
6Sai Life Sciences
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Hadas Tamir
32Israel Institute of Biological Research
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36Lhasa Ltd. UK
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Andrew Thompson
4University of Oxford
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Warren Thompson
2Diamond Light Source Ltd; Research Complex at Harwell
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Susana Tomasio
37Collaborative Drug Discovery
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4University of Oxford
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4University of Oxford
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30Radboud University Medical Center
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30Radboud University Medical Center
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37Collaborative Drug Discovery
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32Israel Institute of Biological Research
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22Temple University
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4University of Oxford
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Frank von Delft
38Diamond Light Source Ltd; University of Oxford; Research Complex at Harwell; University of Johannesburg
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Martin Walsh
2Diamond Light Source Ltd; Research Complex at Harwell
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39Walter Ward Consultancy … Training
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37Collaborative Drug Discovery
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Shay Weiss
32Israel Institute of Biological Research
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Conor Francis Wild
4University of Oxford
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9Memorial Sloan Kettering Cancer Center
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Nathan Wright
4University of Oxford
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Yfat Yahalom-Ronen
32Israel Institute of Biological Research
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Daniel Zaidmann
3The Weizmann Institute of Science
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Hadeer Zidane
3The Weizmann Institute of Science
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Nicole Zitzmann
4University of Oxford
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Abstract

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.

Footnotes

  • ↵1 Full list of authors: https://tinyurl.com/y3r7redd

  • https://postera.ai/covid

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 30, 2020.
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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
The COVID Moonshot Consortium, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L Bobby, Juliane Brun, BVNBS Sarma, 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 Gorrie-Stone, Edward J Griffen, Jag Heer, Michelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Tobias John, Anastassia L. Kantsadi, Peter W. Kenny, John 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 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 Schofield, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Assa Sittner, Rachael 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
bioRxiv 2020.10.29.339317; doi: https://doi.org/10.1101/2020.10.29.339317
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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
The COVID Moonshot Consortium, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L Bobby, Juliane Brun, BVNBS Sarma, 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 Gorrie-Stone, Edward J Griffen, Jag Heer, Michelle Hill, Sam Horrell, Matthew F.D. Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Tobias John, Anastassia L. Kantsadi, Peter W. Kenny, John 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 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 Schofield, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Assa Sittner, Rachael 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
bioRxiv 2020.10.29.339317; doi: https://doi.org/10.1101/2020.10.29.339317

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