tetano
Editor, Senior Moderator
Science
. 2023 Nov 10;382(6671):eabo7201.
doi: 10.1126/science.abo7201. Epub 2023 Nov 10. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Melissa L Boby[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Daren Fearon[SUP] #[/SUP][SUP] 4 5 [/SUP], Matteo Ferla[SUP] #[/SUP][SUP] 6 [/SUP], Mihajlo Filep[SUP] #[/SUP][SUP] 7 [/SUP], Lizbé Koekemoer[SUP] #[/SUP][SUP] 8 9 [/SUP], Matthew C Robinson[SUP] #[/SUP][SUP] 10 [/SUP]; COVID Moonshot Consortium‡; John D Chodera[SUP] 3 [/SUP], Alpha A Lee[SUP] 10 [/SUP], Nir London[SUP] 7 [/SUP], Annette von Delft[SUP] 6 8 9 [/SUP], Frank von Delft[SUP] 4 5 8 9 11 [/SUP], Hagit Achdout[SUP] 12 [/SUP], Anthony Aimon[SUP] 13 14 [/SUP], Dominic S Alonzi[SUP] 15 [/SUP], Robert Arbon[SUP] 16 [/SUP], Jasmin C Aschenbrenner[SUP] 13 14 [/SUP], Blake H Balcomb[SUP] 13 14 [/SUP], Elad Bar-David[SUP] 12 [/SUP], Haim Barr[SUP] 17 [/SUP], Amir Ben-Shmuel[SUP] 12 [/SUP], James Bennett[SUP] 18 19 [/SUP], Vitaliy A Bilenko[SUP] 20 21 [/SUP], Bruce Borden[SUP] 22 [/SUP], Pascale Boulet[SUP] 23 [/SUP], Gregory R Bowman[SUP] 24 [/SUP], Lennart Brewitz[SUP] 25 [/SUP], Juliane Brun[SUP] 15 [/SUP], Sarma Bvnbs[SUP] 26 [/SUP], Mark Calmiano[SUP] 27 [/SUP], Anna Carbery[SUP] 13 28 [/SUP], Daniel W Carney[SUP] 29 [/SUP], Emma Cattermole[SUP] 15 [/SUP], Edcon Chang[SUP] 29 [/SUP], Eugene Chernyshenko[SUP] 20 [/SUP], Austin Clyde[SUP] 30 [/SUP], Joseph E Coffland[SUP] 31 [/SUP], Galit Cohen[SUP] 17 [/SUP], Jason C Cole[SUP] 32 [/SUP], Alessandro Contini[SUP] 33 [/SUP], Lisa Cox[SUP] 34 [/SUP], Tristan Ian Croll[SUP] 35 36 [/SUP], Milan Cvitkovic[SUP] 37 [/SUP], Steven De Jonghe[SUP] 38 [/SUP], Alex Dias[SUP] 13 14 [/SUP], Kim Donckers[SUP] 38 [/SUP], David L Dotson[SUP] 39 [/SUP], Alice Douangamath[SUP] 13 14 [/SUP], Shirly Duberstein[SUP] 17 [/SUP], Tim Dudgeon[SUP] 40 [/SUP], Louise E Dunnett[SUP] 13 14 [/SUP], Peter Eastman[SUP] 41 [/SUP], Noam Erez[SUP] 12 [/SUP], Charles J Eyermann[SUP] 42 [/SUP], Michael Fairhead[SUP] 18 [/SUP], Gwen Fate[SUP] 43 [/SUP], Oleg Fedorov[SUP] 18 19 [/SUP], Rafaela S Fernandes[SUP] 44 [/SUP], Lori Ferrins[SUP] 42 [/SUP], Richard Foster[SUP] 45 [/SUP], Holly Foster[SUP] 45 46 [/SUP], Laurent Fraisse[SUP] 23 [/SUP], Ronen Gabizon[SUP] 47 [/SUP], Adolfo García-Sastre[SUP] 48 49 50 51 52 [/SUP], Victor O Gawriljuk[SUP] 44 53 [/SUP], Paul Gehrtz[SUP] 47 54 [/SUP], Carina Gileadi[SUP] 18 [/SUP], Charline Giroud[SUP] 18 19 [/SUP], William G Glass[SUP] 16 46 [/SUP], Robert C Glen[SUP] 55 [/SUP], Itai Glinert[SUP] 12 [/SUP], Andre S Godoy[SUP] 44 [/SUP], Marian Gorichko[SUP] 21 [/SUP], Tyler Gorrie-Stone[SUP] 13 14 [/SUP], Ed J Griffen[SUP] 56 [/SUP], Amna Haneef[SUP] 57 [/SUP], Storm Hassell Hart[SUP] 58 [/SUP], Jag Heer[SUP] 59 [/SUP], Michael Henry[SUP] 16 [/SUP], Michelle Hill[SUP] 15 60 [/SUP], Sam Horrell[SUP] 13 14 [/SUP], Qiu Yu Judy Huang[SUP] 61 [/SUP], Victor D Huliak[SUP] 20 [/SUP], Matthew F D Hurley[SUP] 62 [/SUP], Tomer Israely[SUP] 12 [/SUP], Andrew Jajack[SUP] 37 [/SUP], Jitske Jansen[SUP] 63 [/SUP], Eric Jnoff[SUP] 64 [/SUP], Dirk Jochmans[SUP] 38 [/SUP], Tobias John[SUP] 25 65 [/SUP], Benjamin Kaminow[SUP] 16 66 [/SUP], Lulu Kang[SUP] 67 [/SUP], Anastassia L Kantsadi[SUP] 15 68 [/SUP], Peter W Kenny[SUP] 69 [/SUP], J L Kiappes[SUP] 15 70 [/SUP], Serhii O Kinakh[SUP] 20 [/SUP], Boris Kovar[SUP] 71 [/SUP], Tobias Krojer[SUP] 18 72 [/SUP], Van Ngoc Thuy La[SUP] 57 [/SUP], Sophie Laghnimi-Hahn[SUP] 23 [/SUP], Bruce A Lefker[SUP] 43 [/SUP], Haim Levy[SUP] 12 [/SUP], Ryan M Lithgo[SUP] 13 14 [/SUP], Ivan G Logvinenko[SUP] 20 [/SUP], Petra Lukacik[SUP] 13 14 [/SUP], Hannah Bruce Macdonald[SUP] 16 73 [/SUP], Elizabeth M MacLean[SUP] 18 [/SUP], Laetitia L Makower[SUP] 15 [/SUP], Tika R Malla[SUP] 18 [/SUP], Peter G Marples[SUP] 13 14 [/SUP], Tatiana Matviiuk[SUP] 20 [/SUP], Willam McCorkindale[SUP] 73 74 [/SUP], Briana L McGovern[SUP] 48 49 [/SUP], Sharon Melamed[SUP] 12 [/SUP], Kostiantyn P Melnykov[SUP] 20 21 [/SUP], Oleg Michurin[SUP] 20 [/SUP], Pascal Miesen[SUP] 75 [/SUP], Halina Mikolajek[SUP] 13 14 [/SUP], Bruce F Milne[SUP] 76 77 [/SUP], David Minh[SUP] 78 [/SUP], Aaron Morris[SUP] 37 [/SUP], Garrett M Morris[SUP] 28 [/SUP], Melody Jane Morwitzer[SUP] 79 [/SUP], Demetri Moustakas[SUP] 80 [/SUP], Charles E Mowbray[SUP] 23 [/SUP], Aline M Nakamura[SUP] 44 81 [/SUP], Jose Brandao Neto[SUP] 13 14 [/SUP], Johan Neyts[SUP] 38 [/SUP], Luong Nguyen[SUP] 37 [/SUP], Gabriela D Noske[SUP] 44 [/SUP], Vladas Oleinikovas[SUP] 27 82 [/SUP], Glaucius Oliva[SUP] 44 [/SUP], Gijs J Overheul[SUP] 75 [/SUP], C David Owen[SUP] 13 14 [/SUP], Ruby Pai[SUP] 37 [/SUP], Jin Pan[SUP] 37 [/SUP], Nir Paran[SUP] 12 [/SUP], Alexander Matthew Payne[SUP] 16 66 [/SUP], Benjamin Perry[SUP] 23 83 [/SUP], Maneesh Pingle[SUP] 26 [/SUP], Jakir Pinjari[SUP] 26 84 [/SUP], Boaz Politi[SUP] 12 [/SUP], Ailsa Powell[SUP] 13 14 [/SUP], Vladimír Pšenák[SUP] 71 [/SUP], Iván Pulido[SUP] 16 [/SUP], Reut Puni[SUP] 12 [/SUP], Victor L Rangel[SUP] 85 86 [/SUP], Rambabu N Reddi[SUP] 47 [/SUP], Paul Rees[SUP] 87 [/SUP], St Patrick Reid[SUP] 79 [/SUP], Lauren Reid[SUP] 56 [/SUP], Efrat Resnick[SUP] 47 [/SUP], Emily Grace Ripka[SUP] 37 [/SUP], Ralph P Robinson[SUP] 43 [/SUP], Jaime Rodriguez-Guerra[SUP] 88 [/SUP], Romel Rosales[SUP] 48 49 [/SUP], Dominic A Rufa[SUP] 16 66 [/SUP], Kadi Saar[SUP] 74 [/SUP], Kumar Singh Saikatendu[SUP] 29 [/SUP], Eidarus Salah[SUP] 25 [/SUP], David Schaller[SUP] 88 [/SUP], Jenke Scheen[SUP] 16 [/SUP], Celia A Schiffer[SUP] 61 [/SUP], Christopher J Schofield[SUP] 25 [/SUP], Mikhail Shafeev[SUP] 20 [/SUP], Aarif Shaikh[SUP] 26 [/SUP], Ala M Shaqra[SUP] 61 [/SUP], Jiye Shi[SUP] 64 89 [/SUP], Khriesto Shurrush[SUP] 17 [/SUP], Sukrit Singh[SUP] 16 [/SUP], Assa Sittner[SUP] 12 [/SUP], Peter Sjö[SUP] 23 [/SUP], Rachael Skyner[SUP] 13 14 [/SUP], Adam Smalley[SUP] 27 [/SUP], Bart Smeets[SUP] 90 [/SUP], Mihaela D Smilova[SUP] 18 [/SUP], Leonardo J Solmesky[SUP] 17 [/SUP], John Spencer[SUP] 58 [/SUP], Claire Strain-Damerell[SUP] 13 14 [/SUP], Vishwanath Swamy[SUP] 26 91 [/SUP], Hadas Tamir[SUP] 12 [/SUP], Jenny C Taylor[SUP] 92 [/SUP], Rachael E Tennant[SUP] 93 [/SUP], Warren Thompson[SUP] 13 14 [/SUP], Andrew Thompson[SUP] 18 94 [/SUP], Susana Tomásio[SUP] 95 [/SUP], Charles W E Tomlinson[SUP] 13 14 [/SUP], Igor S Tsurupa[SUP] 20 [/SUP], Anthony Tumber[SUP] 25 [/SUP], Ioannis Vakonakis[SUP] 15 96 [/SUP], Ronald P van Rij[SUP] 75 [/SUP], Laura Vangeel[SUP] 38 [/SUP], Finny S Varghese[SUP] 75 97 [/SUP], Mariana Vaschetto[SUP] 95 [/SUP], Einat B Vitner[SUP] 12 [/SUP], Vincent Voelz[SUP] 62 [/SUP], Andrea Volkamer[SUP] 88 98 [/SUP], Martin A Walsh[SUP] 13 14 [/SUP], Walter Ward[SUP] 99 [/SUP], Charlie Weatherall[SUP] 100 [/SUP], Shay Weiss[SUP] 12 [/SUP], Kris M White[SUP] 48 49 [/SUP], Conor Francis Wild[SUP] 13 14 [/SUP], Karolina D Witt[SUP] 101 [/SUP], Matthew Wittmann[SUP] 16 [/SUP], Nathan Wright[SUP] 18 [/SUP], Yfat Yahalom-Ronen[SUP] 12 [/SUP], Nese Kurt Yilmaz[SUP] 61 [/SUP], Daniel Zaidmann[SUP] 47 [/SUP], Ivy Zhang[SUP] 16 [/SUP], Hadeer Zidane[SUP] 17 [/SUP], Nicole Zitzmann[SUP] 15 [/SUP], Sarah N Zvornicanin[SUP] 61 [/SUP]
Affiliations
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.
. 2023 Nov 10;382(6671):eabo7201.
doi: 10.1126/science.abo7201. Epub 2023 Nov 10. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Melissa L Boby[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Daren Fearon[SUP] #[/SUP][SUP] 4 5 [/SUP], Matteo Ferla[SUP] #[/SUP][SUP] 6 [/SUP], Mihajlo Filep[SUP] #[/SUP][SUP] 7 [/SUP], Lizbé Koekemoer[SUP] #[/SUP][SUP] 8 9 [/SUP], Matthew C Robinson[SUP] #[/SUP][SUP] 10 [/SUP]; COVID Moonshot Consortium‡; John D Chodera[SUP] 3 [/SUP], Alpha A Lee[SUP] 10 [/SUP], Nir London[SUP] 7 [/SUP], Annette von Delft[SUP] 6 8 9 [/SUP], Frank von Delft[SUP] 4 5 8 9 11 [/SUP], Hagit Achdout[SUP] 12 [/SUP], Anthony Aimon[SUP] 13 14 [/SUP], Dominic S Alonzi[SUP] 15 [/SUP], Robert Arbon[SUP] 16 [/SUP], Jasmin C Aschenbrenner[SUP] 13 14 [/SUP], Blake H Balcomb[SUP] 13 14 [/SUP], Elad Bar-David[SUP] 12 [/SUP], Haim Barr[SUP] 17 [/SUP], Amir Ben-Shmuel[SUP] 12 [/SUP], James Bennett[SUP] 18 19 [/SUP], Vitaliy A Bilenko[SUP] 20 21 [/SUP], Bruce Borden[SUP] 22 [/SUP], Pascale Boulet[SUP] 23 [/SUP], Gregory R Bowman[SUP] 24 [/SUP], Lennart Brewitz[SUP] 25 [/SUP], Juliane Brun[SUP] 15 [/SUP], Sarma Bvnbs[SUP] 26 [/SUP], Mark Calmiano[SUP] 27 [/SUP], Anna Carbery[SUP] 13 28 [/SUP], Daniel W Carney[SUP] 29 [/SUP], Emma Cattermole[SUP] 15 [/SUP], Edcon Chang[SUP] 29 [/SUP], Eugene Chernyshenko[SUP] 20 [/SUP], Austin Clyde[SUP] 30 [/SUP], Joseph E Coffland[SUP] 31 [/SUP], Galit Cohen[SUP] 17 [/SUP], Jason C Cole[SUP] 32 [/SUP], Alessandro Contini[SUP] 33 [/SUP], Lisa Cox[SUP] 34 [/SUP], Tristan Ian Croll[SUP] 35 36 [/SUP], Milan Cvitkovic[SUP] 37 [/SUP], Steven De Jonghe[SUP] 38 [/SUP], Alex Dias[SUP] 13 14 [/SUP], Kim Donckers[SUP] 38 [/SUP], David L Dotson[SUP] 39 [/SUP], Alice Douangamath[SUP] 13 14 [/SUP], Shirly Duberstein[SUP] 17 [/SUP], Tim Dudgeon[SUP] 40 [/SUP], Louise E Dunnett[SUP] 13 14 [/SUP], Peter Eastman[SUP] 41 [/SUP], Noam Erez[SUP] 12 [/SUP], Charles J Eyermann[SUP] 42 [/SUP], Michael Fairhead[SUP] 18 [/SUP], Gwen Fate[SUP] 43 [/SUP], Oleg Fedorov[SUP] 18 19 [/SUP], Rafaela S Fernandes[SUP] 44 [/SUP], Lori Ferrins[SUP] 42 [/SUP], Richard Foster[SUP] 45 [/SUP], Holly Foster[SUP] 45 46 [/SUP], Laurent Fraisse[SUP] 23 [/SUP], Ronen Gabizon[SUP] 47 [/SUP], Adolfo García-Sastre[SUP] 48 49 50 51 52 [/SUP], Victor O Gawriljuk[SUP] 44 53 [/SUP], Paul Gehrtz[SUP] 47 54 [/SUP], Carina Gileadi[SUP] 18 [/SUP], Charline Giroud[SUP] 18 19 [/SUP], William G Glass[SUP] 16 46 [/SUP], Robert C Glen[SUP] 55 [/SUP], Itai Glinert[SUP] 12 [/SUP], Andre S Godoy[SUP] 44 [/SUP], Marian Gorichko[SUP] 21 [/SUP], Tyler Gorrie-Stone[SUP] 13 14 [/SUP], Ed J Griffen[SUP] 56 [/SUP], Amna Haneef[SUP] 57 [/SUP], Storm Hassell Hart[SUP] 58 [/SUP], Jag Heer[SUP] 59 [/SUP], Michael Henry[SUP] 16 [/SUP], Michelle Hill[SUP] 15 60 [/SUP], Sam Horrell[SUP] 13 14 [/SUP], Qiu Yu Judy Huang[SUP] 61 [/SUP], Victor D Huliak[SUP] 20 [/SUP], Matthew F D Hurley[SUP] 62 [/SUP], Tomer Israely[SUP] 12 [/SUP], Andrew Jajack[SUP] 37 [/SUP], Jitske Jansen[SUP] 63 [/SUP], Eric Jnoff[SUP] 64 [/SUP], Dirk Jochmans[SUP] 38 [/SUP], Tobias John[SUP] 25 65 [/SUP], Benjamin Kaminow[SUP] 16 66 [/SUP], Lulu Kang[SUP] 67 [/SUP], Anastassia L Kantsadi[SUP] 15 68 [/SUP], Peter W Kenny[SUP] 69 [/SUP], J L Kiappes[SUP] 15 70 [/SUP], Serhii O Kinakh[SUP] 20 [/SUP], Boris Kovar[SUP] 71 [/SUP], Tobias Krojer[SUP] 18 72 [/SUP], Van Ngoc Thuy La[SUP] 57 [/SUP], Sophie Laghnimi-Hahn[SUP] 23 [/SUP], Bruce A Lefker[SUP] 43 [/SUP], Haim Levy[SUP] 12 [/SUP], Ryan M Lithgo[SUP] 13 14 [/SUP], Ivan G Logvinenko[SUP] 20 [/SUP], Petra Lukacik[SUP] 13 14 [/SUP], Hannah Bruce Macdonald[SUP] 16 73 [/SUP], Elizabeth M MacLean[SUP] 18 [/SUP], Laetitia L Makower[SUP] 15 [/SUP], Tika R Malla[SUP] 18 [/SUP], Peter G Marples[SUP] 13 14 [/SUP], Tatiana Matviiuk[SUP] 20 [/SUP], Willam McCorkindale[SUP] 73 74 [/SUP], Briana L McGovern[SUP] 48 49 [/SUP], Sharon Melamed[SUP] 12 [/SUP], Kostiantyn P Melnykov[SUP] 20 21 [/SUP], Oleg Michurin[SUP] 20 [/SUP], Pascal Miesen[SUP] 75 [/SUP], Halina Mikolajek[SUP] 13 14 [/SUP], Bruce F Milne[SUP] 76 77 [/SUP], David Minh[SUP] 78 [/SUP], Aaron Morris[SUP] 37 [/SUP], Garrett M Morris[SUP] 28 [/SUP], Melody Jane Morwitzer[SUP] 79 [/SUP], Demetri Moustakas[SUP] 80 [/SUP], Charles E Mowbray[SUP] 23 [/SUP], Aline M Nakamura[SUP] 44 81 [/SUP], Jose Brandao Neto[SUP] 13 14 [/SUP], Johan Neyts[SUP] 38 [/SUP], Luong Nguyen[SUP] 37 [/SUP], Gabriela D Noske[SUP] 44 [/SUP], Vladas Oleinikovas[SUP] 27 82 [/SUP], Glaucius Oliva[SUP] 44 [/SUP], Gijs J Overheul[SUP] 75 [/SUP], C David Owen[SUP] 13 14 [/SUP], Ruby Pai[SUP] 37 [/SUP], Jin Pan[SUP] 37 [/SUP], Nir Paran[SUP] 12 [/SUP], Alexander Matthew Payne[SUP] 16 66 [/SUP], Benjamin Perry[SUP] 23 83 [/SUP], Maneesh Pingle[SUP] 26 [/SUP], Jakir Pinjari[SUP] 26 84 [/SUP], Boaz Politi[SUP] 12 [/SUP], Ailsa Powell[SUP] 13 14 [/SUP], Vladimír Pšenák[SUP] 71 [/SUP], Iván Pulido[SUP] 16 [/SUP], Reut Puni[SUP] 12 [/SUP], Victor L Rangel[SUP] 85 86 [/SUP], Rambabu N Reddi[SUP] 47 [/SUP], Paul Rees[SUP] 87 [/SUP], St Patrick Reid[SUP] 79 [/SUP], Lauren Reid[SUP] 56 [/SUP], Efrat Resnick[SUP] 47 [/SUP], Emily Grace Ripka[SUP] 37 [/SUP], Ralph P Robinson[SUP] 43 [/SUP], Jaime Rodriguez-Guerra[SUP] 88 [/SUP], Romel Rosales[SUP] 48 49 [/SUP], Dominic A Rufa[SUP] 16 66 [/SUP], Kadi Saar[SUP] 74 [/SUP], Kumar Singh Saikatendu[SUP] 29 [/SUP], Eidarus Salah[SUP] 25 [/SUP], David Schaller[SUP] 88 [/SUP], Jenke Scheen[SUP] 16 [/SUP], Celia A Schiffer[SUP] 61 [/SUP], Christopher J Schofield[SUP] 25 [/SUP], Mikhail Shafeev[SUP] 20 [/SUP], Aarif Shaikh[SUP] 26 [/SUP], Ala M Shaqra[SUP] 61 [/SUP], Jiye Shi[SUP] 64 89 [/SUP], Khriesto Shurrush[SUP] 17 [/SUP], Sukrit Singh[SUP] 16 [/SUP], Assa Sittner[SUP] 12 [/SUP], Peter Sjö[SUP] 23 [/SUP], Rachael Skyner[SUP] 13 14 [/SUP], Adam Smalley[SUP] 27 [/SUP], Bart Smeets[SUP] 90 [/SUP], Mihaela D Smilova[SUP] 18 [/SUP], Leonardo J Solmesky[SUP] 17 [/SUP], John Spencer[SUP] 58 [/SUP], Claire Strain-Damerell[SUP] 13 14 [/SUP], Vishwanath Swamy[SUP] 26 91 [/SUP], Hadas Tamir[SUP] 12 [/SUP], Jenny C Taylor[SUP] 92 [/SUP], Rachael E Tennant[SUP] 93 [/SUP], Warren Thompson[SUP] 13 14 [/SUP], Andrew Thompson[SUP] 18 94 [/SUP], Susana Tomásio[SUP] 95 [/SUP], Charles W E Tomlinson[SUP] 13 14 [/SUP], Igor S Tsurupa[SUP] 20 [/SUP], Anthony Tumber[SUP] 25 [/SUP], Ioannis Vakonakis[SUP] 15 96 [/SUP], Ronald P van Rij[SUP] 75 [/SUP], Laura Vangeel[SUP] 38 [/SUP], Finny S Varghese[SUP] 75 97 [/SUP], Mariana Vaschetto[SUP] 95 [/SUP], Einat B Vitner[SUP] 12 [/SUP], Vincent Voelz[SUP] 62 [/SUP], Andrea Volkamer[SUP] 88 98 [/SUP], Martin A Walsh[SUP] 13 14 [/SUP], Walter Ward[SUP] 99 [/SUP], Charlie Weatherall[SUP] 100 [/SUP], Shay Weiss[SUP] 12 [/SUP], Kris M White[SUP] 48 49 [/SUP], Conor Francis Wild[SUP] 13 14 [/SUP], Karolina D Witt[SUP] 101 [/SUP], Matthew Wittmann[SUP] 16 [/SUP], Nathan Wright[SUP] 18 [/SUP], Yfat Yahalom-Ronen[SUP] 12 [/SUP], Nese Kurt Yilmaz[SUP] 61 [/SUP], Daniel Zaidmann[SUP] 47 [/SUP], Ivy Zhang[SUP] 16 [/SUP], Hadeer Zidane[SUP] 17 [/SUP], Nicole Zitzmann[SUP] 15 [/SUP], Sarah N Zvornicanin[SUP] 61 [/SUP]
Affiliations
- PMID: 37943932
- DOI: 10.1126/science.abo7201
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.