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
  • 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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