Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

作者：A. Douangamath, D. Fearon, Paul Gehrtz, Tobias J. Krojer, Petra Lukacik, David Owen, Efrat Resnick, Claire M. Strain-Damerell, A. Aimon, Péter Ábrányi‐Balogh, José Brandão‐Neto, Anna Carbery, Gemma Davison, Alexandre M.M. Dias, Thomas D. Downes, Louise E. Dunnett, M. Fairhead, James D. Firth, Simon P. Jones, Aaron Keely, György Miklós Keserű, Hanna F. Klein, Mathew P. Martin, Martin E. M. Noble, Peter O’Brien, A.J. Powell, Rambabu N. Reddi, R. Skyner, M. Snee, Michael J. Waring, Conor Francis Wild, Nir London, F. von Delft, Martin Austin Walsh · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2020 · DOI：10.1101/2020.05.27.118117 · 被引用次数：74 · 研究领域：Computational Drug Discovery Methods、SARS-CoV-2 and COVID-19 Research、RNA and protein synthesis mechanisms

Summary COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.