Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors-Reference-Cited by-同舟云学术

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

Published:2023-11-10 Issue:6671 Volume:382 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Boby Melissa L.¹²³,Fearon Daren⁴⁵^ORCID,Ferla Matteo⁶,Filep Mihajlo⁷^ORCID,Koekemoer Lizbé⁸⁹^ORCID,Robinson Matthew C.¹⁰^ORCID,Chodera John D.³^ORCID,Lee Alpha A.¹⁰,London Nir⁷^ORCID,von Delft Annette⁶⁸⁹^ORCID,von Delft Frank⁴⁵⁸⁹¹¹^ORCID,Achdout Hagit¹²,Aimon Anthony¹³¹⁴,Alonzi Dominic S.¹⁵,Arbon Robert¹⁶,Aschenbrenner Jasmin C.¹³¹⁴,Balcomb Blake H.¹³¹⁴,Bar-David Elad¹²,Barr Haim¹⁷,Ben-Shmuel Amir¹²,Bennett James¹⁸¹⁹,Bilenko Vitaliy A.²⁰²¹,Borden Bruce²²,Boulet Pascale²³,Bowman Gregory R.²⁴,Brewitz Lennart²⁵,Brun Juliane¹⁵,BVNBS Sarma²⁶,Calmiano Mark²⁷,Carbery Anna¹³²⁸,Carney Daniel W.²⁹,Cattermole Emma¹⁵,Chang Edcon²⁹,Chernyshenko Eugene²⁰,Clyde Austin³⁰,Coffland Joseph E.³¹,Cohen Galit¹⁷,Cole Jason C.³²,Contini Alessandro³³,Cox Lisa³⁴,Croll Tristan Ian³⁵³⁶,Cvitkovic Milan³⁷,De Jonghe Steven³⁸,Dias Alex¹³¹⁴,Donckers Kim³⁸,Dotson David L.³⁹,Douangamath Alice¹³¹⁴,Duberstein Shirly¹⁷,Dudgeon Tim⁴⁰,Dunnett Louise E.¹³¹⁴,Eastman Peter⁴¹,Erez Noam¹²,Eyermann Charles J.⁴²,Fairhead Michael¹⁸,Fate Gwen⁴³,Fedorov Oleg¹⁸¹⁹,Fernandes Rafaela S.⁴⁴,Ferrins Lori⁴²,Foster Richard⁴⁵,Foster Holly⁴⁵⁴⁶,Fraisse Laurent²³,Gabizon Ronen⁴⁷,García-Sastre Adolfo⁴⁸⁴⁹⁵⁰⁵¹⁵²,Gawriljuk Victor O.⁴⁴⁵³,Gehrtz Paul⁴⁷⁵⁴,Gileadi Carina¹⁸,Giroud Charline¹⁸¹⁹,Glass William G.¹⁶⁴⁶,Glen Robert C.⁵⁵,Glinert Itai¹²,Godoy Andre S.⁴⁴,Gorichko Marian²¹,Gorrie-Stone Tyler¹³¹⁴,Griffen Ed J.⁵⁶,Haneef Amna⁵⁷,Hassell Hart Storm⁵⁸,Heer Jag⁵⁹,Henry Michael¹⁶,Hill Michelle¹⁵⁶⁰,Horrell Sam¹³¹⁴,Huang Qiu Yu Judy⁶¹,Huliak Victor D.²⁰,Hurley Matthew F. D.⁶²,Israely Tomer¹²,Jajack Andrew³⁷,Jansen Jitske⁶³,Jnoff Eric⁶⁴,Jochmans Dirk³⁸,John Tobias²⁵⁶⁵,Kaminow Benjamin¹⁶⁶⁶,Kang Lulu⁶⁷,Kantsadi Anastassia L.¹⁵⁶⁸,Kenny Peter W.⁶⁹,Kiappes J. L.¹⁵⁷⁰,Kinakh Serhii O.²⁰,Kovar Boris⁷¹,Krojer Tobias¹⁸⁷²,La Van Ngoc Thuy⁵⁷,Laghnimi-Hahn Sophie²³,Lefker Bruce A.⁴³,Levy Haim¹²,Lithgo Ryan M.¹³¹⁴,Logvinenko Ivan G.²⁰,Lukacik Petra¹³¹⁴,Macdonald Hannah Bruce¹⁶⁷³,MacLean Elizabeth M.¹⁸,Makower Laetitia L.¹⁵,Malla Tika R.¹⁸,Marples Peter G.¹³¹⁴,Matviiuk Tatiana²⁰,McCorkindale Willam⁷³⁷⁴,McGovern Briana L.⁴⁸⁴⁹,Melamed Sharon¹²,Melnykov Kostiantyn P.²⁰²¹,Michurin Oleg²⁰,Miesen Pascal⁷⁵,Mikolajek Halina¹³¹⁴,Milne Bruce F.⁷⁶⁷⁷,Minh David⁷⁸,Morris Aaron³⁷,Morris Garrett M.²⁸,Morwitzer Melody Jane⁷⁹,Moustakas Demetri⁸⁰,Mowbray Charles E.²³,Nakamura Aline M.⁴⁴⁸¹,Neto Jose Brandao¹³¹⁴,Neyts Johan³⁸,Nguyen Luong³⁷,Noske Gabriela D.⁴⁴,Oleinikovas Vladas²⁷⁸²,Oliva Glaucius⁴⁴,Overheul Gijs J.⁷⁵,Owen C. David¹³¹⁴,Pai Ruby³⁷,Pan Jin³⁷,Paran Nir¹²,Payne Alexander Matthew¹⁶⁶⁶,Perry Benjamin²³⁸³,Pingle Maneesh²⁶,Pinjari Jakir²⁶⁸⁴,Politi Boaz¹²,Powell Ailsa¹³¹⁴,Pšenák Vladimír⁷¹,Pulido Iván¹⁶,Puni Reut¹²,Rangel Victor L.⁸⁵⁸⁶,Reddi Rambabu N.⁴⁷,Rees Paul⁸⁷,Reid St Patrick⁷⁹,Reid Lauren⁵⁶,Resnick Efrat⁴⁷,Ripka Emily Grace³⁷,Robinson Ralph P.⁴³,Rodriguez-Guerra Jaime⁸⁸,Rosales Romel⁴⁸⁴⁹,Rufa Dominic A.¹⁶⁶⁶,Saar Kadi⁷⁴,Saikatendu Kumar Singh²⁹,Salah Eidarus²⁵,Schaller David⁸⁸,Scheen Jenke¹⁶,Schiffer Celia A.⁶¹,Schofield Christopher J.²⁵,Shafeev Mikhail²⁰,Shaikh Aarif²⁶,Shaqra Ala M.⁶¹,Shi Jiye⁶⁴⁸⁹,Shurrush Khriesto¹⁷,Singh Sukrit¹⁶,Sittner Assa¹²,Sjö Peter²³,Skyner Rachael¹³¹⁴,Smalley Adam²⁷,Smeets Bart⁹⁰,Smilova Mihaela D.¹⁸,Solmesky Leonardo J.¹⁷,Spencer John⁵⁸,Strain-Damerell Claire¹³¹⁴,Swamy Vishwanath²⁶⁹¹,Tamir Hadas¹²,Taylor Jenny C.⁹²,Tennant Rachael E.⁹³,Thompson Warren¹³¹⁴,Thompson Andrew¹⁸⁹⁴,Tomásio Susana⁹⁵,Tomlinson Charles W. E.¹³¹⁴,Tsurupa Igor S.²⁰,Tumber Anthony²⁵,Vakonakis Ioannis¹⁵⁹⁶,van Rij Ronald P.⁷⁵,Vangeel Laura³⁸,Varghese Finny S.⁷⁵⁹⁷,Vaschetto Mariana⁹⁵,Vitner Einat B.¹²,Voelz Vincent⁶²,Volkamer Andrea⁸⁸⁹⁸,Walsh Martin A.¹³¹⁴,Ward Walter⁹⁹,Weatherall Charlie¹⁰⁰,Weiss Shay¹²,White Kris M.⁴⁸⁴⁹,Wild Conor Francis¹³¹⁴,Witt Karolina D.¹⁰¹,Wittmann Matthew¹⁶,Wright Nathan¹⁸,Yahalom-Ronen Yfat¹²,Yilmaz Nese Kurt⁶¹,Zaidmann Daniel⁴⁷,Zhang Ivy¹⁶,Zidane Hadeer¹⁷,Zitzmann Nicole¹⁵,Zvornicanin Sarah N.⁶¹,

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.abo7201

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