Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
A. Douangamath, D. Fearon, Paul Gehrtz, Tobias J. Krojer, Petra Lukacik, David Owen, Efrat Resnick, Claire M. Strain-Damerell, A. Aimon, Péter Ábrányi‐Balogh, J. 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 B. Keeley · Nature Communications · 2020
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 were 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.