Produção Nacional
Revisado por pares
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
2023; American Association for the Advancement of Science; Volume: 382; Issue: 6671 Linguagem: Inglês
10.1126/science.abo7201
ISSN1095-9203
AutoresMelissa L. Boby, D. Fearon, Matteo P. Ferla, Mihajlo Filep, L. Koekemoer, Matthew C. Robinson, John D. Chodera, Alpha A. Lee, Nir London, Annette von Delft, F. von Delft, Hagit Achdout, A. Aimon, Dominic S. Alonzi, Robert Arbon, Jasmin C. Aschenbrenner, Blake H. Balcomb, Elad Bar-David, Haim Barr, Amir Ben‐Shmuel, James M. Bennett, Vitaliy A. Bilenko, Bruce Borden, Pascale Boulet, Gregory R. Bowman, Lennart Brewitz, Juliane Brun, Sarma BVNBS, Mark Calmiano, Anna Carbery, Daniel W. Carney, Emma Cattermole, Edcon Chang, Eugene Chernyshenko, Austin Clyde, Joseph E. Coffland, Galit Cohen, Jason C. Cole, Alessandro Contini, Lisa Sanderson Cox, Tristan I. Croll, Milan Cvitkovic, Steven De Jonghe, Alex Dias, Kim Donckers, David Dotson, A. Douangamath, Shirly Duberstein, Tim Dudgeon, Louise E. Dunnett, Peter Eastman, Noam Erez, Charles J. Eyermann, M. Fairhead, Gwen Fate, O. Fedorov, R.S. Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Laurent Fraisse, Ronen Gabizon, Adolfo Garcı́a-Sastre, Victor O. Gawriljuk, Paul Gehrtz, C. Gileadi, Charline Giroud, William G. Glass, Robert C. Glen, Itai Glinert, André S. Godoy, Marian V. Gorichko, T.J. Gorrie-Stone, Ed Griffen, Amna Haneef, Storm Hassell Hart, Jag Heer, Michael M. Henry, Michelle L. Hill, Sam Horrell, Qiu Yu J. Huang, Victor D. Huliak, Matthew F. D. Hurley, Tomer Israely, Andrew Jajack, Jitske Jansen, Eric Jnoff, Dirk Jochmans, Tobias John, Benjamin Kaminow, Lulu Kang, A.L. Kantsadi, Peter W. Kenny, J. L. Kiappes, Serhii O. Kinakh, Boris Kovar, T. Krojer, Van Ngoc Thuy La, Sophie Laghnimi-Hahn, Bruce A. Lefker, Haim Levy, Ryan M. Lithgo, Ivan G. Logvinenko, Petra Lukacik, Hannah Bruce Macdonald, Elizabeth MacLean, Laetitia L. Makower, Tika R. Malla, Peter Marples, Tatiana Matviiuk, Willam McCorkindale, Briana L. McGovern, Sharon Melamed, Kostiantyn P. Melnykov, Oleg Michurin, Pascal Miesen, Halina Mikolajek, Bruce F. Milne, David D. L. Minh, Aaron Morris, Garrett M. Morris, M. Jane Morwitzer, Demetri Moustakas, Charles E. Mowbray, A.M. Nakamura, José Brandão Neto, Johan Neyts, Luong Viet Nguyen, G.D. Noske, Vladas Oleinikovas, Glaucius Oliva, Gijs J. Overheul, David Owen, Ruby Pai, Jin Pan, Nir Paran, Alexander Matthew Payne, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, A.J. Powell, Vladimír Pšenák, Iván Pulido, Reut Puni, V.L. Rangel, Rambabu Reddi, Paul Rees, St Patrick Reid, Lauren M. Reid, Efrat Resnick, Emily Grace Ripka, Ralph P. Robinson, Jaime Rodrı́guez-Guerra, Romel Rosales, Dominic A. Rufa, Kadi L. Saar, Kumar Singh Saikatendu, E. Salah, David Schaller, Jenke Scheen, Celia A. Schiffer, Christopher J. Schofield, Mikhail Shafeev, Aarif Shaikh, Ala M. Shaqra, Jiye Shi, Khriesto A. Shurrush, Sukrit Singh, Assa Sittner, Peter Sjö, R. Skyner, Adam P. Smalley, Bart Smeets, Mihaela Smilova, Leonardo J. Solmesky, John Spencer, Claire Strain‐Damerell, Vishwanath Swamy, Hadas Tamir, Jenny C. Taylor, Rachael E. Tennant, Warren Thompson, Andrew Thompson, Susana Tomásio, Charles W. Tomlinson, Igor S. Tsurupa, Anthony Tumber, Ioannis Vakonakis, Ronald P. van Rij, Laura Vangeel, Finny S. Varghese, M. Vaschetto, Einat B. Vitner, Vincent A. Voelz, Andrea Volkamer, Martin Walsh, Walter H.J. Ward, Charlie Weatherall, Shay Weiss, Kris M. White, Conor Wild, Karolina D. Witt, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Neşe Kurt Yılmaz, Daniel Zaidmann, Ivy Zhang, Hadeer Zidane, Nicole Zitzmann, Sarah N. Zvornicanin,
Tópico(s)SARS-CoV-2 and COVID-19 Research
ResumoWe 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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