Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking-Reference-Cited by-同舟云学术

Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking

Published:2020-11-24 Issue: Volume: Page:
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Schuller Marion^ORCID,Correy Galen J.^ORCID,Gahbauer Stefan^ORCID,Fearon Daren^ORCID,Wu Taiasean^ORCID,Díaz Roberto Efraín^ORCID,Young Iris D.^ORCID,Martins Luan Carvalho^ORCID,Smith Dominique H.,Schulze-Gahmen Ursula^ORCID,Owens Tristan W.^ORCID,Deshpande Ishan^ORCID,Merz Gregory E.^ORCID,Thwin Aye C.^ORCID,Biel Justin T.^ORCID,Peters Jessica K.^ORCID,Moritz Michelle^ORCID,Herrera Nadia^ORCID,Kratochvil Huong T.^ORCID,Aimon Anthony^ORCID,Bennett James M.^ORCID,Neto Jose Brandao^ORCID,Cohen Aina E.^ORCID,Dias Alexandre^ORCID,Douangamath Alice^ORCID,Dunnett Louise^ORCID,Fedorov Oleg^ORCID,Ferla Matteo P.^ORCID,Fuchs Martin^ORCID,Gorrie-Stone Tyler J.^ORCID,Holton James M.^ORCID,Johnson Michael G.,Krojer Tobias^ORCID,Meigs George,Powell Ailsa J.^ORCID,Rack Johannes Gregor Matthias^ORCID,Rangel Victor L^ORCID,Russi Silvia^ORCID,Skyner Rachael E.^ORCID,Smith Clyde A.^ORCID,Soares Alexei S.^ORCID,Wierman Jennifer L.^ORCID,Zhu Kang^ORCID,Jura Natalia^ORCID,Ashworth Alan^ORCID,Irwin John^ORCID,Thompson Michael C.^ORCID,Gestwicki Jason E.^ORCID,von Delft Frank^ORCID,Shoichet Brian K.^ORCID,Fraser James S.^ORCID,Ahel Ivan^ORCID,

Abstract

ABSTRACTThe SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Publisher

Cold Spring Harbor Laboratory

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