Peer-Reviewed Publication
Science2023;382(6671):eabo7201.November 10, 2023Journal Article
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.
Melissa L Boby1,2,3, Daren Fearon4,5, Matteo Ferla6, Mihajlo Filep7, Lizbé Koekemoer8,9, Matthew C Robinson10, , John D Chodera3, Alpha A Lee10, Nir London7, Annette von Delft6,8,9, Frank von Delft4,5,8,9,11, Hagit Achdout12, Anthony Aimon13,14, Dominic S Alonzi15, Robert Arbon16, Jasmin C Aschenbrenner13,14, Blake H Balcomb13,14, Elad Bar-David12, Haim Barr17, Amir Ben-Shmuel12, James Bennett18,19, Vitaliy A Bilenko20,21, Bruce Borden22, Pascale Boulet23, Gregory R Bowman24, Lennart Brewitz25, Juliane Brun15, Sarma Bvnbs26, Mark Calmiano27, Anna Carbery13,28, Daniel W Carney29, Emma Cattermole15, Edcon Chang29, Eugene Chernyshenko20, Austin Clyde30, Joseph E Coffland31, Galit Cohen17, Jason C Cole32, Alessandro Contini33, Lisa Cox34, Tristan Ian Croll35,36, Milan Cvitkovic37, Steven De Jonghe38, Alex Dias13,14, Kim Donckers38, David L Dotson39, Alice Douangamath13,14, Shirly Duberstein17, Tim Dudgeon40, Louise E Dunnett13,14, Peter Eastman41, Noam Erez12, Charles J Eyermann42, Michael Fairhead18, Gwen Fate43, Oleg Fedorov18,19, Rafaela S Fernandes44, Lori Ferrins42, Richard Foster45, Holly Foster45,46, Laurent Fraisse23, Ronen Gabizon47, Adolfo García-Sastre48,49,50,51,52, Victor O Gawriljuk44,53, Paul Gehrtz47,54, Carina Gileadi18, Charline Giroud18,19, William G Glass16,46, Robert C Glen55, Itai Glinert12, Andre S Godoy44, Marian Gorichko21, Tyler Gorrie-Stone13,14, Ed J Griffen56, Amna Haneef57, Storm Hassell Hart58, Jag Heer59, Michael Henry16, Michelle Hill15,60, Sam Horrell13,14, Qiu Yu Judy Huang61, Victor D Huliak20, Matthew F D Hurley62, Tomer Israely12, Andrew Jajack37, Jitske Jansen63, Eric Jnoff64, Dirk Jochmans38, Tobias John25,65, Benjamin Kaminow16,66, Lulu Kang67, Anastassia L Kantsadi15,68, Peter W Kenny69, J L Kiappes15,70, Serhii O Kinakh20, Boris Kovar71, Tobias Krojer18,72, Van Ngoc Thuy La57, Sophie Laghnimi-Hahn23, Bruce A Lefker43, Haim Levy12, Ryan M Lithgo13,14, Ivan G Logvinenko20, Petra Lukacik13,14, Hannah Bruce Macdonald16,73, Elizabeth M MacLean18, Laetitia L Makower15, Tika R Malla18, Peter G Marples13,14, Tatiana Matviiuk20, Willam McCorkindale73,74, Briana L McGovern48,49, Sharon Melamed12, Kostiantyn P Melnykov20,21, Oleg Michurin20, Pascal Miesen75, Halina Mikolajek13,14, Bruce F Milne76,77, David Minh78, Aaron Morris37, Garrett M Morris28, Melody Jane Morwitzer79, Demetri Moustakas80, Charles E Mowbray23, Aline M Nakamura44,81, Jose Brandao Neto13,14, Johan Neyts38, Luong Nguyen37, Gabriela D Noske44, Vladas Oleinikovas27,82, Glaucius Oliva44, Gijs J Overheul75, C David Owen13,14, Ruby Pai37, Jin Pan37, Nir Paran12, Alexander Matthew Payne16,66, Benjamin Perry23,83, Maneesh Pingle26, Jakir Pinjari26,84, Boaz Politi12, Ailsa Powell13,14, Vladimír Pšenák71, Iván Pulido16, Reut Puni12, Victor L Rangel85,86, Rambabu N Reddi47, Paul Rees87, St Patrick Reid79, Lauren Reid56, Efrat Resnick47, Emily Grace Ripka37, Ralph P Robinson43, Jaime Rodriguez-Guerra88, Romel Rosales48,49, Dominic A Rufa16,66, Kadi Saar74, Kumar Singh Saikatendu29, Eidarus Salah25, David Schaller88, Jenke Scheen16, Celia A Schiffer61, Christopher J Schofield25, Mikhail Shafeev20, Aarif Shaikh26, Ala M Shaqra61, Jiye Shi64,89, Khriesto Shurrush17, Sukrit Singh16, Assa Sittner12, Peter Sjö23, Rachael Skyner13,14, Adam Smalley27, Bart Smeets90, Mihaela D Smilova18, Leonardo J Solmesky17, John Spencer58, Claire Strain-Damerell13,14, Vishwanath Swamy26,91, Hadas Tamir12, Jenny C Taylor92, Rachael E Tennant93, Warren Thompson13,14, Andrew Thompson18,94, Susana Tomásio95, Charles W E Tomlinson13,14, Igor S Tsurupa20, Anthony Tumber25, Ioannis Vakonakis15,96, Ronald P van Rij75, Laura Vangeel38, Finny S Varghese75,97, Mariana Vaschetto95, Einat B Vitner12, Vincent Voelz62, Andrea Volkamer88,98, Martin A Walsh13,14, Walter Ward99, Charlie Weatherall100, Shay Weiss12, Kris M White48,49, Conor Francis Wild13,14, Karolina D Witt101, Matthew Wittmann16, Nathan Wright18, Yfat Yahalom-Ronen12, Nese Kurt Yilmaz61, Daniel Zaidmann47, Ivy Zhang16, Hadeer Zidane17, Nicole Zitzmann15, Sarah N Zvornicanin61
1Pharmacology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
2Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3Program in Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, UK.
5Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK.
6Oxford Biomedical Research Centre, National Institute for Health Research, University of Oxford, Oxford, UK.
7Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, Israel.
8Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
9Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
10PostEra Inc., Cambridge, MA 02142, USA.
11Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa.
12Israel Institute for Biological Research, Department of Infectious Diseases, Ness-Ziona, Israel.
13Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
14Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK.
15University of Oxford, Department of Biochemistry, Oxford Glycobiology Institute, South Parks Road, Oxford OX1 3QU, UK.
16Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, Computational and Systems Biology Program, New York, NY 10065, USA.
17The Weizmann Institute of Science, Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Rehovot, 7610001, Israel.
18University of Oxford, Nuffield Department of Medicine, Centre for Medicines Discovery, Oxford, OX3 7DQ, UK.
19University of Oxford, Nuffield Department of Medicine, Target Discovery Institute, Oxford, OX3 7FZ, UK.
20Enamine Ltd, Kyiv, 02094, Ukraine.
21Taras Shevchenko National University of Kyiv, Kyiv, 01601, Ukraine.
22Folding@Home Consortium.
23Drugs for Neglected Diseases Initiative (DNDi), Geneva, 1202, Switzerland.
24University of Pennsylvania, Departments of Biochemistry and Biophysics and Bioengineering, Philadelphia, PA 19083, USA.
25University of Oxford, Department of Chemistry, Chemistry Research Laboratory, Oxford, OX1 3TA, UK.
26Sai Life Sciences Limited, ICICI Knowledge Park, Shameerpet, Hyderabad 500 078, Telangana, India.
27UCB, Slough, SL1 3WE, UK.
28University of Oxford, Department of Statistics, Oxford OX1 3LB, UK.
29Takeda Development Center Americas, Inc., San Diego, CA 92121, USA.
30Argonne National Lab, Lemont, IL 60439, USA.
31Cauldron Development Oy, Helsinki, 00140, Finland.
32Cambridge Crystallographic Data Centre, Cambridge, CB2 1EZ, UK.
33University of Milan, Department of General and Organic Chemistry, Milan, 20133, Italy.
34Life Compass Consulting Ltd, Macclesfield, SK10 5UE, UK.
35The University of Cambridge, Cambridge Institute for Medical Research, Department of Haematology, Cambridge CB2 0XY, UK.
36Present address: Altos Labs, BioML group, Great Abington, CB21 6GP.
37PostEra Inc., Cambridge, MA, 02142, USA.
38KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
39Datryllic LLC, Phoenix AZ, 85003, USA.
40Informatics Matters Ltd, Bicester, OX26 6JU, UK.
41Stanford University, Department of Chemistry, Stanford, CA 94305, USA.
42Northeastern University, Department of Chemistry and Chemical Biology, Boston MA 02115, USA.
43Thames Pharma Partners LLC, Mystic, CT 06355, USA.
44University of Sao Paulo, Sao Carlos Institute of Physics, Sao Carlos, 13563-120, Brazil.
45University of Leeds, School of Chemistry, Leeds, LS2 9JT, UK.
46Present address: Exscientia, Oxford Science Park, Oxford, OX4 4GE, UK.
47The Weizmann Institute of Science, Department of Chemical and Structural Biology, Rehovot, 7610001, Israel.
48Icahn School of Medicine at Mount Sinai, Department of Microbiology, New York, NY 10029, USA.
49Icahn School of Medicine at Mount Sinai, Global Health and Emerging Pathogens Institute, New York, NY 10029, USA.
50Icahn School of Medicine at Mount Sinai, Department of Medicine, Division of Infectious Diseases, New York, NY 10029, USA.
51Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY 10029, USA.
52Icahn School of Medicine at Mount Sinai, Department of Pathology, Molecular and Cell-Based Medicine, New York, NY 10029, USA.
53Present address: University of Groningen, Groningen Research Institute of Pharmacy, Department of Drug Design, Groningen, 9700 AV, Netherlands.
54Present address: Merck Healthcare KGaA, Darmstadt, 64293, Germany.
55University of Cambridge, Department of Chemistry, Cambridge, CB2 1EW, UK.
56MedChemica Ltd, Macclesfield, Cheshire. SK11 6PU UK.
57Illinois Institute of Technology, Department of Biology, Chicago IL 60616 USA.
58University of Sussex, Department of Chemistry, School of Life Sciences, Brighton, East Sussex, BN1 9QJ, UK.
59Syngene International Limited, Headington, Oxford, OX3 7BZ, UK.
60Present address: Sir William Dunn School of Pathology, Oxford. OX1 3RE, UK.
61University of Massachusetts, Chan Medical School, Department of Biochemistry and Molecular Biotechnology, Worcester MA 01655, USA.
62Temple University, Department of Chemistry, Philadelphia, PA 19122, USA.
63RWTH Aachen University, Institute of Experimental Medicine and Systems Biology, Aachen, 52074, Germany.
64UCB, Chemin du Foriest, 1420 Braine-l'Alleud, Belgium.
65Present address: AMSilk, Neuried, 82061, Germany.
66Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, Tri-Institutional Program in Computational Biology and Medicine, New York, NY 10065, USA.
67Illinois Institute of Technology, Department of Applied Mathematics, Chicago IL 60616 USA.
68University of Thessaly, Department of Biochemistry and Biotechnology, Larissa, 415 00, Greece.
69Berwick-on-Sea, North Coast Road, Blanchisseuse, Saint George, Trinidad and Tobago.
70Present address: University College of London, Department of Chemistry, London WC1H 0AJ, UK.
71M2M solutions s.r.o. Žilina, 010 01, Slovakia.
72MAX IV Laboratory, Fotongatan 2, 224 84 Lund, Sweden.
73Present address: Charm Therapeutics, London, N1C 4AG, UK.
74University of Cambridge, Cavendish Laboratory, Cambridge, CB3 0HE UK.
75Radboud University Medical Center, Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Nijmegen, 6525 GA, Netherlands.
76University of Aberdeen, Department of Chemistry, Old Aberdeen, AB24 3UE Scotland, UK.
77University of Coimbra, CFisUC, Department of Physics, Coimbra, 3004-516, Portugal.
78Illinois Institute of Technology, Department of Chemistry, Chicago IL 60616 USA.
79University of Nebraska Medical Centre, Dept of Pathology and Microbiology, Omaha, NE 68198-5900, USA.
80Relay Therapeutics, Cambridge, MA 02139, USA.
81Present address: Instituto Butantan, Sao Paulo, 05503-900, Brazil.
82Present address: Monte Rosa Therapeutics, Basel, CH 4057, Switzerland.
83Present address: Medicxi, Geneva, 1204, Switzerland.
84Present address: Sun Pharma Advanced Research Company (SPARC), Baroda, India.
85University of São Paulo, Ribeirão Preto School of Pharmaceutical Sciences, Ribeirão Preto - SP/CEP 14040-903, Brazil.
86Present address: Evotec (UK) Ltd, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK.
87Compass Bussiness Partners Ltd, Southcliffe, Bucks, SL9 0PD, UK.
88Charité - Universitätsmedizin Berlin, In silico Toxicology and Structural Bioinformatics, Berlin, 10117, Germany.
89Present address: Eli Lilly and Company, San Diego, CA 92121, USA.
90Radboud University Medical Center, Department of pathology, Radboud Institute for Molecular Life Sciences, Nijmegen, 6525 GA, Netherlands.
91Present address: TCG Life Sciences, Pune, India.
92University of Oxford, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, Oxford OX3 7BN, UK.
93Lhasa Limited, Leeds, LS11 5PS, UK.
94Present address: Walter and Eliza Hall Institute, Parkville 3052, Victoria, Australia.
95Collaborative Drug Discovery, Cambridge, CB2 1GE, UK.
96Present address: Lonza Biologics, Lonza Ltd, Lonzastrasse, CH-3930 Visp, Switzerland.
97Present address: uniQure Biopharma, Amsterdam, 1105 BP, Netherlands.
98Present address: Saarland University, Data Driven Drug Design, Campus - E2.1, 66123 Saarbrücken, Germany.
99Walter Ward Consultancy and Training, Derbyshire, SK22 4AA, UK.
100Collaborative Drug Discovery, Burlingame, CA 94010, USA.
101University of Oxford, Nuffield Department of Medicine, Pandemic Sciences Institute, Oxford, Oxon, OX3 7DQ, UK.
Abstract
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 crowdsourcin…
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