De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens. [Display omitted] •De novo designed a series of potent SARS-CoV-2 main protease inhibitors•The designed DMBK warhead has a characteristic binding mode•These inhibitors provide new clues for the drug design of cysteine proteases Zhu et al. report a series of de novo-designed SARS-CoV-2 main protease inhibitors that have a characteristic binding mode and potent inhibitory activity. High-resolution structures show that the designed dibromomethyl ketone warhead can interact with SARS-CoV-2 main protease through covalent bond and π-π stacking interaction.