Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Douangamath A., Fearon D., Gehrtz P., Krojer T., Lukacik P., Owen CD., Resnick E., Strain-Damerell C., Aimon A., Ábrányi-Balogh P., Brandão-Neto J., Carbery A., Davison G., Dias A., Downes TD., Dunnett L., Fairhead M., Firth JD., Jones SP., Keeley A., Keserü GM., Klein HF., Martin MP., Noble MEM., O'Brien P., Powell A., Reddi RN., Skyner R., Snee M., Waring MJ., Wild C., London N., von Delft F., Walsh MA.
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.