The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C‐like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands’ interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50 µM concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.
【저자키워드】 Virology, antivirals, 【초록키워드】 Structure, SARS-CoV-2, drug design, SARS-COV-2 infection, COVID-19 pandemic, antiviral drugs, 3CLpro, docking, protease, in vitro, in silico, SARS-CoV-1, approved drugs, MPro, SARS-CoV-2 Mpro, Viral, cleavage, DrugBank, inhibitor, compounds, Protease activity, Interaction, Concentration, Analysis, crystal structures, focus, active site, FDA-approved drug, Compound, sequence, crystal, residues, library, ChEMBL, inhibitory compounds, inhibitory, SARS-CoV-2 viral, selected, tested, predicted, analyzed, caused, conserved, carried, addition, screened, facilitate, occur, suggested, catalytic, cleavage process, filtered, H-bond interaction, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, coronavirus, Interaction, acute respiratory syndrome, required,