Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CL pro ) has been regarded as an extremely promising antiviral target for the treatment of coronavirus disease 2019 (COVID-19). Here, we carried out a virtual screening based on commercial compounds database to find novel covalent non-peptidomimetic inhibitors of this protease. It allowed us to identify 3 hit compounds with potential covalent binding modes, which were evaluated through an enzymatic activity assay of the SARS-CoV-2 3CL pro . Moreover, an X-ray crystal structure of the SARS-CoV-2 3CL pro in complex with compound 8, the most potent hit with an IC 50 value of 8.50 μM, confirmed the covalent binding of the predicted warhead to the catalytic residue C145, as well as portrayed interactions of the compound with S1′ and S2 subsites at the ligand binding pocket. Overall, the present work not merely provided an experiment-validated covalent hit targeting the SARS-CoV-2 3CL pro , but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach.
Keywords: Covalent inhibitor; Crystal structure; SARS-CoV-2 3C-Like protease; Virtual screening.
【저자키워드】 covalent inhibitor, virtual screening., crystal structure, SARS-CoV-2 3C-Like protease, 【초록키워드】 COVID-19, Treatment, coronavirus disease, SARS-CoV-2, Coronavirus disease 2019, coronavirus, Virtual screening, 3CL pro, protease, severe acute respiratory syndrome Coronavirus, database, X-ray, small molecule, crystal structure, inhibitor, antiviral target, 3CL, Interaction, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, enzymatic activity, complex, residue, Compound, crystal, covalent binding, approach, effective, ligand binding pocket, predicted, identify, example, carried, evaluated, provided, feasible, catalytic, seeking, the SARS-CoV-2, 【제목키워드】 inhibitor, 3CL, the SARS-CoV-2,