7GJG

Group deposition SARS-CoV-2 main protease in complex with inhibitors from the COVID Moonshot -- Crystal Structure of SARS-CoV-2 main protease in complex with ALP-UNI-8e43a71e-8 (Mpro-P0238)

Summary for 7GJG

• Entry DOI: 10.2210/pdb7gjg/pdb
• Group deposition: Group deposition SARS-CoV-2 main protease in complex with inhibitors from the COVID Moonshot (G_1002272)
• Descriptor: 3C-like proteinase, DIMETHYL SULFOXIDE, (4S)-6-chloro-4-{2-[4-(3-hydroxypropyl)piperazin-1-yl]-2-oxoethyl}-N-(isoquinolin-4-yl)-3,4-dihydro-2H-1-benzopyran-4-carboxamide, ... (4 entities in total)
• Functional Keywords: diamond light source, i04-1, covid moonshot, cmd, mpro, fragment screening, pandda, xchemexplorer, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68564.78

Authors

Fearon, D.,Aimon, A.,Aschenbrenner, J.C.,Balcomb, B.H.,Bertram, F.K.R.,Brandao-Neto, J.,Dias, A.,Douangamath, A.,Dunnett, L.,Godoy, A.S.,Gorrie-Stone, T.J.,Koekemoer, L.,Krojer, T.,Lithgo, R.M.,Lukacik, P.,Marples, P.G.,Mikolajek, H.,Nelson, E.,Owen, C.D.,Powell, A.J.,Rangel, V.L.,Skyner, R.,Strain-Damerell, C.M.,Thompson, W.,Tomlinson, C.W.E.,Wild, C.,Walsh, M.A.,von Delft, F. (deposition date: 2023-08-11, release date: 2023-11-08, Last modification date: 2023-12-06)

Primary citation

Boby, M.L.,Fearon, D.,Ferla, M.,Filep, M.,Koekemoer, L.,Robinson, M.C.,Chodera, J.D.,Lee, A.A.,London, N.,von Delft, A.,von Delft, F.,Achdout, H.,Aimon, A.,Alonzi, D.S.,Arbon, R.,Aschenbrenner, J.C.,Balcomb, B.H.,Bar-David, E.,Barr, H.,Ben-Shmuel, A.,Bennett, J.,Bilenko, V.A.,Borden, B.,Boulet, P.,Bowman, G.R.,Brewitz, L.,Brun, J.,Bvnbs, S.,Calmiano, M.,Carbery, A.,Carney, D.W.,Cattermole, E.,Chang, E.,Chernyshenko, E.,Clyde, A.,Coffland, J.E.,Cohen, G.,Cole, J.C.,Contini, A.,Cox, L.,Croll, T.I.,Cvitkovic, M.,De Jonghe, S.,Dias, A.,Donckers, K.,Dotson, D.L.,Douangamath, A.,Duberstein, S.,Dudgeon, T.,Dunnett, L.E.,Eastman, P.,Erez, N.,Eyermann, C.J.,Fairhead, M.,Fate, G.,Fedorov, O.,Fernandes, R.S.,Ferrins, L.,Foster, R.,Foster, H.,Fraisse, L.,Gabizon, R.,Garcia-Sastre, A.,Gawriljuk, V.O.,Gehrtz, P.,Gileadi, C.,Giroud, C.,Glass, W.G.,Glen, R.C.,Glinert, I.,Godoy, A.S.,Gorichko, M.,Gorrie-Stone, T.,Griffen, E.J.,Haneef, A.,Hassell Hart, S.,Heer, J.,Henry, M.,Hill, M.,Horrell, S.,Huang, Q.Y.J.,Huliak, V.D.,Hurley, M.F.D.,Israely, T.,Jajack, A.,Jansen, J.,Jnoff, E.,Jochmans, D.,John, T.,Kaminow, B.,Kang, L.,Kantsadi, A.L.,Kenny, P.W.,Kiappes, J.L.,Kinakh, S.O.,Kovar, B.,Krojer, T.,La, V.N.T.,Laghnimi-Hahn, S.,Lefker, B.A.,Levy, H.,Lithgo, R.M.,Logvinenko, I.G.,Lukacik, P.,Macdonald, H.B.,MacLean, E.M.,Makower, L.L.,Malla, T.R.,Marples, P.G.,Matviiuk, T.,McCorkindale, W.,McGovern, B.L.,Melamed, S.,Melnykov, K.P.,Michurin, O.,Miesen, P.,Mikolajek, H.,Milne, B.F.,Minh, D.,Morris, A.,Morris, G.M.,Morwitzer, M.J.,Moustakas, D.,Mowbray, C.E.,Nakamura, A.M.,Neto, J.B.,Neyts, J.,Nguyen, L.,Noske, G.D.,Oleinikovas, V.,Oliva, G.,Overheul, G.J.,Owen, C.D.,Pai, R.,Pan, J.,Paran, N.,Payne, A.M.,Perry, B.,Pingle, M.,Pinjari, J.,Politi, B.,Powell, A.,Psenak, V.,Pulido, I.,Puni, R.,Rangel, V.L.,Reddi, R.N.,Rees, P.,Reid, S.P.,Reid, L.,Resnick, E.,Ripka, E.G.,Robinson, R.P.,Rodriguez-Guerra, J.,Rosales, R.,Rufa, D.A.,Saar, K.,Saikatendu, K.S.,Salah, E.,Schaller, D.,Scheen, J.,Schiffer, C.A.,Schofield, C.J.,Shafeev, M.,Shaikh, A.,Shaqra, A.M.,Shi, J.,Shurrush, K.,Singh, S.,Sittner, A.,Sjo, P.,Skyner, R.,Smalley, A.,Smeets, B.,Smilova, M.D.,Solmesky, L.J.,Spencer, J.,Strain-Damerell, C.,Swamy, V.,Tamir, H.,Taylor, J.C.,Tennant, R.E.,Thompson, W.,Thompson, A.,Tomasio, S.,Tomlinson, C.W.E.,Tsurupa, I.S.,Tumber, A.,Vakonakis, I.,van Rij, R.P.,Vangeel, L.,Varghese, F.S.,Vaschetto, M.,Vitner, E.B.,Voelz, V.,Volkamer, A.,Walsh, M.A.,Ward, W.,Weatherall, C.,Weiss, S.,White, K.M.,Wild, C.F.,Witt, K.D.,Wittmann, M.,Wright, N.,Yahalom-Ronen, Y.,Yilmaz, N.K.,Zaidmann, D.,Zhang, I.,Zidane, H.,Zitzmann, N.,Zvornicanin, S.N.
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.
Science, 382:eabo7201-eabo7201, 2023

PubMed 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.

PubMed: 37943932
DOI: 10.1126/science.abo7201

Experimental method

X-RAY DIFFRACTION (1.99 Å)