2. Academic Validation
  3. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

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

  • Science. 2023 Nov 10;382(6671):eabo7201. doi: 10.1126/science.abo7201.
Melissa L Boby # 1 2 3,  Daren Fearon # 4 5,  Matteo Ferla # 6,  Mihajlo Filep # 7,  Lizbé Koekemoer # 8 9,  Matthew C Robinson # 10,  COVID Moonshot Consortium‡,  John D Chodera 3,  Alpha A Lee 10,  Nir London 7,  Annette von Delft 6 8 9,  Frank von Delft 4 5 8 9 11,  Hagit Achdout 12,  Anthony Aimon 13 14,  Dominic S Alonzi 15,  Robert Arbon 16,  Jasmin C Aschenbrenner 13 14,  Blake H Balcomb 13 14,  Elad Bar-David 12,  Haim Barr 17,  Amir Ben-Shmuel 12,  James Bennett 18 19,  Vitaliy A Bilenko 20 21,  Bruce Borden 22,  Pascale Boulet 23,  Gregory R Bowman 24,  Lennart Brewitz 25,  Juliane Brun 15,  Sarma Bvnbs 26,  Mark Calmiano 27,  Anna Carbery 13 28,  Daniel W Carney 29,  Emma Cattermole 15,  Edcon Chang 29,  Eugene Chernyshenko 20,  Austin Clyde 30,  Joseph E Coffland 31,  Galit Cohen 17,  Jason C Cole 32,  Alessandro Contini 33,  Lisa Cox 34,  Tristan Ian Croll 35 36,  Milan Cvitkovic 37,  Steven De Jonghe 38,  Alex Dias 13 14,  Kim Donckers 38,  David L Dotson 39,  Alice Douangamath 13 14,  Shirly Duberstein 17,  Tim Dudgeon 40,  Louise E Dunnett 13 14,  Peter Eastman 41,  Noam Erez 12,  Charles J Eyermann 42,  Michael Fairhead 18,  Gwen Fate 43,  Oleg Fedorov 18 19,  Rafaela S Fernandes 44,  Lori Ferrins 42,  Richard Foster 45,  Holly Foster 45 46,  Laurent Fraisse 23,  Ronen Gabizon 47,  Adolfo García-Sastre 48 49 50 51 52,  Victor O Gawriljuk 44 53,  Paul Gehrtz 47 54,  Carina Gileadi 18,  Charline Giroud 18 19,  William G Glass 16 46,  Robert C Glen 55,  Itai Glinert 12,  Andre S Godoy 44,  Marian Gorichko 21,  Tyler Gorrie-Stone 13 14,  Ed J Griffen 56,  Amna Haneef 57,  Storm Hassell Hart 58,  Jag Heer 59,  Michael Henry 16,  Michelle Hill 15 60,  Sam Horrell 13 14,  Qiu Yu Judy Huang 61,  Victor D Huliak 20,  Matthew F D Hurley 62,  Tomer Israely 12,  Andrew Jajack 37,  Jitske Jansen 63,  Eric Jnoff 64,  Dirk Jochmans 38,  Tobias John 25 65,  Benjamin Kaminow 16 66,  Lulu Kang 67,  Anastassia L Kantsadi 15 68,  Peter W Kenny 69,  J L Kiappes 15 70,  Serhii O Kinakh 20,  Boris Kovar 71,  Tobias Krojer 18 72,  Van Ngoc Thuy La 57,  Sophie Laghnimi-Hahn 23,  Bruce A Lefker 43,  Haim Levy 12,  Ryan M Lithgo 13 14,  Ivan G Logvinenko 20,  Petra Lukacik 13 14,  Hannah Bruce Macdonald 16 73,  Elizabeth M MacLean 18,  Laetitia L Makower 15,  Tika R Malla 18,  Peter G Marples 13 14,  Tatiana Matviiuk 20,  Willam McCorkindale 73 74,  Briana L McGovern 48 49,  Sharon Melamed 12,  Kostiantyn P Melnykov 20 21,  Oleg Michurin 20,  Pascal Miesen 75,  Halina Mikolajek 13 14,  Bruce F Milne 76 77,  David Minh 78,  Aaron Morris 37,  Garrett M Morris 28,  Melody Jane Morwitzer 79,  Demetri Moustakas 80,  Charles E Mowbray 23,  Aline M Nakamura 44 81,  Jose Brandao Neto 13 14,  Johan Neyts 38,  Luong Nguyen 37,  Gabriela D Noske 44,  Vladas Oleinikovas 27 82,  Glaucius Oliva 44,  Gijs J Overheul 75,  C David Owen 13 14,  Ruby Pai 37,  Jin Pan 37,  Nir Paran 12,  Alexander Matthew Payne 16 66,  Benjamin Perry 23 83,  Maneesh Pingle 26,  Jakir Pinjari 26 84,  Boaz Politi 12,  Ailsa Powell 13 14,  Vladimír Pšenák 71,  Iván Pulido 16,  Reut Puni 12,  Victor L Rangel 85 86,  Rambabu N Reddi 47,  Paul Rees 87,  St Patrick Reid 79,  Lauren Reid 56,  Efrat Resnick 47,  Emily Grace Ripka 37,  Ralph P Robinson 43,  Jaime Rodriguez-Guerra 88,  Romel Rosales 48 49,  Dominic A Rufa 16 66,  Kadi Saar 74,  Kumar Singh Saikatendu 29,  Eidarus Salah 25,  David Schaller 88,  Jenke Scheen 16,  Celia A Schiffer 61,  Christopher J Schofield 25,  Mikhail Shafeev 20,  Aarif Shaikh 26,  Ala M Shaqra 61,  Jiye Shi 64 89,  Khriesto Shurrush 17,  Sukrit Singh 16,  Assa Sittner 12,  Peter Sjö 23,  Rachael Skyner 13 14,  Adam Smalley 27,  Bart Smeets 90,  Mihaela D Smilova 18,  Leonardo J Solmesky 17,  John Spencer 58,  Claire Strain-Damerell 13 14,  Vishwanath Swamy 26 91,  Hadas Tamir 12,  Jenny C Taylor 92,  Rachael E Tennant 93,  Warren Thompson 13 14,  Andrew Thompson 18 94,  Susana Tomásio 95,  Charles W E Tomlinson 13 14,  Igor S Tsurupa 20,  Anthony Tumber 25,  Ioannis Vakonakis 15 96,  Ronald P van Rij 75,  Laura Vangeel 38,  Finny S Varghese 75 97,  Mariana Vaschetto 95,  Einat B Vitner 12,  Vincent Voelz 62,  Andrea Volkamer 88 98,  Martin A Walsh 13 14,  Walter Ward 99,  Charlie Weatherall 100,  Shay Weiss 12,  Kris M White 48 49,  Conor Francis Wild 13 14,  Karolina D Witt 101,  Matthew Wittmann 16,  Nathan Wright 18,  Yfat Yahalom-Ronen 12,  Nese Kurt Yilmaz 61,  Daniel Zaidmann 47,  Ivy Zhang 16,  Hadeer Zidane 17,  Nicole Zitzmann 15,  Sarah N Zvornicanin 61
Affiliations

Affiliations

  • 1 Pharmacology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
  • 2 Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Program in Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, UK.
  • 5 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK.
  • 6 Oxford Biomedical Research Centre, National Institute for Health Research, University of Oxford, Oxford, UK.
  • 7 Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, Israel.
  • 8 Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 9 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 10 PostEra Inc., Cambridge, MA 02142, USA.
  • 11 Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa.
  • 12 Israel Institute for Biological Research, Department of Infectious Diseases, Ness-Ziona, Israel.
  • 13 Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
  • 14 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK.
  • 15 University of Oxford, Department of Biochemistry, Oxford Glycobiology Institute, South Parks Road, Oxford OX1 3QU, UK.
  • 16 Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, Computational and Systems Biology Program, New York, NY 10065, USA.
  • 17 The Weizmann Institute of Science, Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Rehovot, 7610001, Israel.
  • 18 University of Oxford, Nuffield Department of Medicine, Centre for Medicines Discovery, Oxford, OX3 7DQ, UK.
  • 19 University of Oxford, Nuffield Department of Medicine, Target Discovery Institute, Oxford, OX3 7FZ, UK.
  • 20 Enamine Ltd, Kyiv, 02094, Ukraine.
  • 21 Taras Shevchenko National University of Kyiv, Kyiv, 01601, Ukraine.
  • 22 Folding@Home Consortium.
  • 23 Drugs for Neglected Diseases Initiative (DNDi), Geneva, 1202, Switzerland.
  • 24 University of Pennsylvania, Departments of Biochemistry and Biophysics and Bioengineering, Philadelphia, PA 19083, USA.
  • 25 University of Oxford, Department of Chemistry, Chemistry Research Laboratory, Oxford, OX1 3TA, UK.
  • 26 Sai Life Sciences Limited, ICICI Knowledge Park, Shameerpet, Hyderabad 500 078, Telangana, India.
  • 27 UCB, Slough, SL1 3WE, UK.
  • 28 University of Oxford, Department of Statistics, Oxford OX1 3LB, UK.
  • 29 Takeda Development Center Americas, Inc., San Diego, CA 92121, USA.
  • 30 Argonne National Lab, Lemont, IL 60439, USA.
  • 31 Cauldron Development Oy, Helsinki, 00140, Finland.
  • 32 Cambridge Crystallographic Data Centre, Cambridge, CB2 1EZ, UK.
  • 33 University of Milan, Department of General and Organic Chemistry, Milan, 20133, Italy.
  • 34 Life Compass Consulting Ltd, Macclesfield, SK10 5UE, UK.
  • 35 The University of Cambridge, Cambridge Institute for Medical Research, Department of Haematology, Cambridge CB2 0XY, UK.
  • 36 Present address: Altos Labs, BioML group, Great Abington, CB21 6GP.
  • 37 PostEra Inc., Cambridge, MA, 02142, USA.
  • 38 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
  • 39 Datryllic LLC, Phoenix AZ, 85003, USA.
  • 40 Informatics Matters Ltd, Bicester, OX26 6JU, UK.
  • 41 Stanford University, Department of Chemistry, Stanford, CA 94305, USA.
  • 42 Northeastern University, Department of Chemistry and Chemical Biology, Boston MA 02115, USA.
  • 43 Thames Pharma Partners LLC, Mystic, CT 06355, USA.
  • 44 University of Sao Paulo, Sao Carlos Institute of Physics, Sao Carlos, 13563-120, Brazil.
  • 45 University of Leeds, School of Chemistry, Leeds, LS2 9JT, UK.
  • 46 Present address: Exscientia, Oxford Science Park, Oxford, OX4 4GE, UK.
  • 47 The Weizmann Institute of Science, Department of Chemical and Structural Biology, Rehovot, 7610001, Israel.
  • 48 Icahn School of Medicine at Mount Sinai, Department of Microbiology, New York, NY 10029, USA.
  • 49 Icahn School of Medicine at Mount Sinai, Global Health and Emerging Pathogens Institute, New York, NY 10029, USA.
  • 50 Icahn School of Medicine at Mount Sinai, Department of Medicine, Division of Infectious Diseases, New York, NY 10029, USA.
  • 51 Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY 10029, USA.
  • 52 Icahn School of Medicine at Mount Sinai, Department of Pathology, Molecular and Cell-Based Medicine, New York, NY 10029, USA.
  • 53 Present address: University of Groningen, Groningen Research Institute of Pharmacy, Department of Drug Design, Groningen, 9700 AV, Netherlands.
  • 54 Present address: Merck Healthcare KGaA, Darmstadt, 64293, Germany.
  • 55 University of Cambridge, Department of Chemistry, Cambridge, CB2 1EW, UK.
  • 56 MedChemica Ltd, Macclesfield, Cheshire. SK11 6PU UK.
  • 57 Illinois Institute of Technology, Department of Biology, Chicago IL 60616 USA.
  • 58 University of Sussex, Department of Chemistry, School of Life Sciences, Brighton, East Sussex, BN1 9QJ, UK.
  • 59 Syngene International Limited, Headington, Oxford, OX3 7BZ, UK.
  • 60 Present address: Sir William Dunn School of Pathology, Oxford. OX1 3RE, UK.
  • 61 University of Massachusetts, Chan Medical School, Department of Biochemistry and Molecular Biotechnology, Worcester MA 01655, USA.
  • 62 Temple University, Department of Chemistry, Philadelphia, PA 19122, USA.
  • 63 RWTH Aachen University, Institute of Experimental Medicine and Systems Biology, Aachen, 52074, Germany.
  • 64 UCB, Chemin du Foriest, 1420 Braine-l'Alleud, Belgium.
  • 65 Present address: AMSilk, Neuried, 82061, Germany.
  • 66 Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, Tri-Institutional Program in Computational Biology and Medicine, New York, NY 10065, USA.
  • 67 Illinois Institute of Technology, Department of Applied Mathematics, Chicago IL 60616 USA.
  • 68 University of Thessaly, Department of Biochemistry and Biotechnology, Larissa, 415 00, Greece.
  • 69 Berwick-on-Sea, North Coast Road, Blanchisseuse, Saint George, Trinidad and Tobago.
  • 70 Present address: University College of London, Department of Chemistry, London WC1H 0AJ, UK.
  • 71 M2M solutions s.r.o. Žilina, 010 01, Slovakia.
  • 72 MAX IV Laboratory, Fotongatan 2, 224 84 Lund, Sweden.
  • 73 Present address: Charm Therapeutics, London, N1C 4AG, UK.
  • 74 University of Cambridge, Cavendish Laboratory, Cambridge, CB3 0HE UK.
  • 75 Radboud University Medical Center, Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Nijmegen, 6525 GA, Netherlands.
  • 76 University of Aberdeen, Department of Chemistry, Old Aberdeen, AB24 3UE Scotland, UK.
  • 77 University of Coimbra, CFisUC, Department of Physics, Coimbra, 3004-516, Portugal.
  • 78 Illinois Institute of Technology, Department of Chemistry, Chicago IL 60616 USA.
  • 79 University of Nebraska Medical Centre, Dept of Pathology and Microbiology, Omaha, NE 68198-5900, USA.
  • 80 Relay Therapeutics, Cambridge, MA 02139, USA.
  • 81 Present address: Instituto Butantan, Sao Paulo, 05503-900, Brazil.
  • 82 Present address: Monte Rosa Therapeutics, Basel, CH 4057, Switzerland.
  • 83 Present address: Medicxi, Geneva, 1204, Switzerland.
  • 84 Present address: Sun Pharma Advanced Research Company (SPARC), Baroda, India.
  • 85 University of São Paulo, Ribeirão Preto School of Pharmaceutical Sciences, Ribeirão Preto - SP/CEP 14040-903, Brazil.
  • 86 Present address: Evotec (UK) Ltd, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK.
  • 87 Compass Bussiness Partners Ltd, Southcliffe, Bucks, SL9 0PD, UK.
  • 88 Charité - Universitätsmedizin Berlin, In silico Toxicology and Structural Bioinformatics, Berlin, 10117, Germany.
  • 89 Present address: Eli Lilly and Company, San Diego, CA 92121, USA.
  • 90 Radboud University Medical Center, Department of pathology, Radboud Institute for Molecular Life Sciences, Nijmegen, 6525 GA, Netherlands.
  • 91 Present address: TCG Life Sciences, Pune, India.
  • 92 University of Oxford, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, Oxford OX3 7BN, UK.
  • 93 Lhasa Limited, Leeds, LS11 5PS, UK.
  • 94 Present address: Walter and Eliza Hall Institute, Parkville 3052, Victoria, Australia.
  • 95 Collaborative Drug Discovery, Cambridge, CB2 1GE, UK.
  • 96 Present address: Lonza Biologics, Lonza Ltd, Lonzastrasse, CH-3930 Visp, Switzerland.
  • 97 Present address: uniQure Biopharma, Amsterdam, 1105 BP, Netherlands.
  • 98 Present address: Saarland University, Data Driven Drug Design, Campus - E2.1, 66123 Saarbrücken, Germany.
  • 99 Walter Ward Consultancy and Training, Derbyshire, SK22 4AA, UK.
  • 100 Collaborative Drug Discovery, Burlingame, CA 94010, USA.
  • 101 University of Oxford, Nuffield Department of Medicine, Pandemic Sciences Institute, Oxford, Oxon, OX3 7DQ, UK.
  • # Contributed equally.
PMID: 37943932 DOI: 10.1126/science.abo7201
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 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.

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