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Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Authors
Boby, Melissa LFearon, Daren
Ferla, Matteo
Filep, Mihajlo
Koekemoer, Lizbé
Robinson, Matthew C
Chodera, John D
Lee, Alpha A
London, Nir
von Delft, Annette
von Delft, Frank
Achdout, Hagit
Aimon, Anthony
Alonzi, Dominic S
Arbon, Robert
Aschenbrenner, Jasmin C
Balcomb, Blake H
Bar-David, Elad
Barr, Haim
Ben-Shmuel, Amir
Bennett, James
Bilenko, Vitaliy A
Borden, Bruce
Boulet, Pascale
Bowman, Gregory R
Brewitz, Lennart
Brun, Juliane
Bvnbs, Sarma
Calmiano, Mark
Carbery, Anna
Carney, Daniel W
Cattermole, Emma
Chang, Edcon
Chernyshenko, Eugene
Clyde, Austin
Coffland, Joseph E
Cohen, Galit
Cole, Jason C
Contini, Alessandro
Cox, Lisa
Croll, Tristan Ian
Cvitkovic, Milan
De Jonghe, Steven
Dias, Alex
Donckers, Kim
Dotson, David L
Douangamath, Alice
Duberstein, Shirly
Dudgeon, Tim
Dunnett, Louise E
Eastman, Peter
Erez, Noam
Eyermann, Charles J
Fairhead, Michael
Fate, Gwen
Fedorov, Oleg
Fernandes, Rafaela S
Ferrins, Lori
Foster, Richard
Foster, Holly
Fraisse, Laurent
Gabizon, Ronen
García-Sastre, Adolfo
Gawriljuk, Victor O
Gehrtz, Paul
Gileadi, Carina
Giroud, Charline
Glass, William G
Glen, Robert C
Glinert, Itai
Godoy, Andre S
Gorichko, Marian
Gorrie-Stone, Tyler
Griffen, Ed J
Haneef, Amna
Hassell Hart, Storm
Heer, Jag
Henry, Michael
Hill, Michelle
Horrell, Sam
Huang, Qiu Yu Judy
Huliak, Victor D
Hurley, Matthew F D
Israely, Tomer
Jajack, Andrew
Jansen, Jitske
Jnoff, Eric
Jochmans, Dirk
John, Tobias
Kaminow, Benjamin
Kang, Lulu
Kantsadi, Anastassia L
Kenny, Peter W
Kiappes, J L
Kinakh, Serhii O
Kovar, Boris
Krojer, Tobias
La, Van Ngoc Thuy
Laghnimi-Hahn, Sophie
Lefker, Bruce A
Levy, Haim
Lithgo, Ryan M
Logvinenko, Ivan G
Lukacik, Petra
Macdonald, Hannah Bruce
MacLean, Elizabeth M
Makower, Laetitia L
Malla, Tika R
Marples, Peter G
Matviiuk, Tatiana
McCorkindale, Willam
McGovern, Briana L
Melamed, Sharon
Melnykov, Kostiantyn P
Michurin, Oleg
Miesen, Pascal
Mikolajek, Halina
Milne, Bruce F
Minh, David
Morris, Aaron
Morris, Garrett M
Morwitzer, Melody Jane
Moustakas, Demetri
Mowbray, Charles E
Nakamura, Aline M
Neto, Jose Brandao
Neyts, Johan
Nguyen, Luong
Noske, Gabriela D
Oleinikovas, Vladas
Oliva, Glaucius
Overheul, Gijs J
Owen, C David
Pai, Ruby
Pan, Jin
Paran, Nir
Payne, Alexander Matthew
Perry, Benjamin
Pingle, Maneesh
Pinjari, Jakir
Politi, Boaz
Powell, Ailsa
Pšenák, Vladimír
Pulido, Iván
Puni, Reut
Rangel, Victor L
Reddi, Rambabu N
Rees, Paul
Reid, St Patrick
Reid, Lauren
Resnick, Efrat
Ripka, Emily Grace
Robinson, Ralph P
Rodriguez-Guerra, Jaime
Rosales, Romel
Rufa, Dominic A
Saar, Kadi
Saikatendu, Kumar Singh
Salah, Eidarus
Schaller, David
Scheen, Jenke
Schiffer, Celia A
Schofield, Christopher J
Shafeev, Mikhail
Shaikh, Aarif
Shaqra, Ala M
Shi, Jiye
Shurrush, Khriesto
Singh, Sukrit
Sittner, Assa
Sjö, Peter
Skyner, Rachael
Smalley, Adam
Smeets, Bart
Smilova, Mihaela D
Solmesky, Leonardo J
Spencer, John
Strain-Damerell, Claire
Swamy, Vishwanath
Tamir, Hadas
Taylor, Jenny C
Tennant, Rachael E
Thompson, Warren
Thompson, Andrew
Tomásio, Susana
Tomlinson, Charles W E
Tsurupa, Igor S
Tumber, Anthony
Vakonakis, Ioannis
van Rij, Ronald P
Vangeel, Laura
Varghese, Finny S
Vaschetto, Mariana
Vitner, Einat B
Voelz, Vincent
Volkamer, Andrea
Walsh, Martin A
Ward, Walter
Weatherall, Charlie
Weiss, Shay
White, Kris M
Wild, Conor Francis
Witt, Karolina D
Wittmann, Matthew
Wright, Nathan
Yahalom-Ronen, Yfat
Yilmaz, Nese Kurt
Zaidmann, Daniel
Zhang, Ivy
Zidane, Hadeer
Zitzmann, Nicole
Zvornicanin, Sarah N
Student Authors
Qiu Yu Judy HuangUMass Chan Affiliations
Biochemistry and Molecular BiotechnologyMorningside Graduate School of Biomedical Sciences
Schiffer Lab
Document Type
Journal ArticlePublication Date
2023-11-10
Metadata
Show full item recordAbstract
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.Source
Boby ML, Fearon D, Ferla M, Filep M, Koekemoer L, Robinson MC; COVID Moonshot Consortium‡; Chodera JD, Lee AA, London N, von Delft A, von Delft F, Achdout H, Aimon A, Alonzi DS, Arbon R, Aschenbrenner JC, Balcomb BH, Bar-David E, Barr H, Ben-Shmuel A, Bennett J, Bilenko VA, Borden B, Boulet P, Bowman GR, Brewitz L, Brun J, Bvnbs S, Calmiano M, Carbery A, Carney DW, Cattermole E, Chang E, Chernyshenko E, Clyde A, Coffland JE, Cohen G, Cole JC, Contini A, Cox L, Croll TI, Cvitkovic M, De Jonghe S, Dias A, Donckers K, Dotson DL, Douangamath A, Duberstein S, Dudgeon T, Dunnett LE, Eastman P, Erez N, Eyermann CJ, Fairhead M, Fate G, Fedorov O, Fernandes RS, Ferrins L, Foster R, Foster H, Fraisse L, Gabizon R, García-Sastre A, Gawriljuk VO, Gehrtz P, Gileadi C, Giroud C, Glass WG, Glen RC, Glinert I, Godoy AS, Gorichko M, Gorrie-Stone T, Griffen EJ, Haneef A, Hassell Hart S, Heer J, Henry M, Hill M, Horrell S, Huang QYJ, Huliak VD, Hurley MFD, Israely T, Jajack A, Jansen J, Jnoff E, Jochmans D, John T, Kaminow B, Kang L, Kantsadi AL, Kenny PW, Kiappes JL, Kinakh SO, Kovar B, Krojer T, La VNT, Laghnimi-Hahn S, Lefker BA, Levy H, Lithgo RM, Logvinenko IG, Lukacik P, Macdonald HB, MacLean EM, Makower LL, Malla TR, Marples PG, Matviiuk T, McCorkindale W, McGovern BL, Melamed S, Melnykov KP, Michurin O, Miesen P, Mikolajek H, Milne BF, Minh D, Morris A, Morris GM, Morwitzer MJ, Moustakas D, Mowbray CE, Nakamura AM, Neto JB, Neyts J, Nguyen L, Noske GD, Oleinikovas V, Oliva G, Overheul GJ, Owen CD, Pai R, Pan J, Paran N, Payne AM, Perry B, Pingle M, Pinjari J, Politi B, Powell A, Pšenák V, Pulido I, Puni R, Rangel VL, Reddi RN, Rees P, Reid SP, Reid L, Resnick E, Ripka EG, Robinson RP, Rodriguez-Guerra J, Rosales R, Rufa DA, Saar K, Saikatendu KS, Salah E, Schaller D, Scheen J, Schiffer CA, Schofield CJ, Shafeev M, Shaikh A, Shaqra AM, Shi J, Shurrush K, Singh S, Sittner A, Sjö P, Skyner R, Smalley A, Smeets B, Smilova MD, Solmesky LJ, Spencer J, Strain-Damerell C, Swamy V, Tamir H, Taylor JC, Tennant RE, Thompson W, Thompson A, Tomásio S, Tomlinson CWE, Tsurupa IS, Tumber A, Vakonakis I, van Rij RP, Vangeel L, Varghese FS, Vaschetto M, Vitner EB, Voelz V, Volkamer A, Walsh MA, Ward W, Weatherall C, Weiss S, White KM, Wild CF, Witt KD, Wittmann M, Wright N, Yahalom-Ronen Y, Yilmaz NK, Zaidmann D, Zhang I, Zidane H, Zitzmann N, Zvornicanin SN. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Science. 2023 Nov 10;382(6671):eabo7201. doi: 10.1126/science.abo7201. Epub 2023 Nov 10. PMID: 37943932.DOI
10.1126/science.abo7201Permanent Link to this Item
http://hdl.handle.net/20.500.14038/52849PubMed ID
37943932ae974a485f413a2113503eed53cd6c53
10.1126/science.abo7201
Scopus Count
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