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.
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors / M.L. Boby, D. Fearon, M. Ferla, M. Filep, L. Koekemoer, M.C. Robinson, J.D. Chodera, A.A. Lee, N. London, A. von Delft, F. von Delft, H. Achdout, A. Aimon, D.S. Alonzi, R. Arbon, J.C. Aschenbrenner, B.H. Balcomb, E. Bar-David, H. Barr, A. Ben-Shmuel, J. Bennett, V.A. Bilenko, B. Borden, P. Boulet, G.R. Bowman, L. Brewitz, J. Brun, S. Bvnbs, M. Calmiano, A. Carbery, D.W. Carney, E. Cattermole, E. Chang, E. Chernyshenko, A. Clyde, J.E. Coffland, G. Cohen, J.C. Cole, A. Contini, L. Cox, T. Ian Croll, M. Cvitkovic, S. De Jonghe, A. Dias, K. Donckers, D.L. Dotson, A. Douangamath, S. Duberstein, T. Dudgeon, L.E. Dunnett, P. Eastman, N. Erez, C.J. Eyermann, M. Fairhead, G. Fate, O. Fedorov, R.S. Fernandes, L. Ferrins, R. Foster, H. Foster, L. Fraisse, R. Gabizon, A. García-Sastre, V.O. Gawriljuk, P. Gehrtz, C. Gileadi, C. Giroud, W.G. Glass, R.C. Glen, I. Glinert, A.S. Godoy, M. Gorichko, T. Gorrie-Stone, E.J. Griffen, A. Haneef, S. Hassell Hart, J. Heer, M. Henry, M. Hill, S. Horrell, Q. Yu Judy Huang, V.D. Huliak, M.F.D. Hurley, T. Israely, A. Jajack, J. Jansen, E. Jnoff, D. Jochmans, T. John, B. Kaminow, L. Kang, A.L. Kantsadi, P.W. Kenny, J.L. Kiappes, S.O. Kinakh, B. Kovar, T. Krojer, V. Ngoc Thuy La, S. Laghnimi-Hahn, B.A. Lefker, H. Levy, R.M. Lithgo, I.G. Logvinenko, P. Lukacik, H. Bruce Macdonald, E.M. Maclean, L.L. Makower, T.R. Malla, P.G. Marples, T. Matviiuk, W. Mccorkindale, B.L. Mcgovern, S. Melamed, K.P. Melnykov, O. Michurin, P. Miesen, H. Mikolajek, B.F. Milne, D. Minh, A. Morris, G.M. Morris, M. Jane Morwitzer, D. Moustakas, C.E. Mowbray, A.M. Nakamura, J. Brandao Neto, J. Neyts, L. Nguyen, G.D. Noske, V. Oleinikovas, G. Oliva, G.J. Overheul, C. David Owen, R. Pai, J. Pan, N. Paran, A. Matthew Payne, B. Perry, M. Pingle, J. Pinjari, B. Politi, A. Powell, V. Pšenák, I. Pulido, R. Puni, V.L. Rangel, R.N. Reddi, P. Rees, S. Patrick Reid, L. Reid, E. Resnick, E. Grace Ripka, R.P. Robinson, J. Rodriguez-Guerra, R. Rosales, D.A. Rufa, K. Saar, K. Singh Saikatendu, E. Salah, D. Schaller, J. Scheen, C.A. Schiffer, C.J. Schofield, M. Shafeev, A. Shaikh, A.M. Shaqra, J. Shi, K. Shurrush, S. Singh, A. Sittner, P. Sjö, R. Skyner, A. Smalley, B. Smeets, M.D. Smilova, L.J. Solmesky, J. Spencer, C. Strain-Damerell, V. Swamy, H. Tamir, J.C. Taylor, R.E. Tennant, W. Thompson, A. Thompson, S. Tomásio, C.W.E. Tomlinson, I.S. Tsurupa, A. Tumber, I. Vakonakis, R.P. van Rij, L. Vangeel, F.S. Varghese, M. Vaschetto, E.B. Vitner, V. Voelz, A. Volkamer, M.A. Walsh, W. Ward, C. Weatherall, S. Weiss, K.M. White, C. Francis Wild, K.D. Witt, M. Wittmann, N. Wright, Y. Yahalom-Ronen, N. Kurt Yilmaz, D. Zaidmann, I. Zhang, H. Zidane, N. Zitzmann, S.N. Zvornicanin. - In: SCIENCE. - ISSN 0036-8075. - 382:6671(2023 Nov 10), pp. 1-19. [10.1126/science.abo7201]
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
A. Contini;
2023
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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