7VVT

SARS-CoV-2 3CL protease (3CLpro) in complex with a covalent inhibitor

Summary for 7VVT

• Entry DOI: 10.2210/pdb7vvt/pdb
• Descriptor: 3C-like proteinase, N-(3-chlorophenyl)-2-[(2R)-1-ethanoyl-3-oxidanylidene-piperazin-2-yl]ethanamide (3 entities in total)
• Functional Keywords: main protease, covalent inhibitor, viral protein-inhibitor complex, viral inhibitor-complex complex, viral inhibitor/complex
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 68270.59

Authors

Su, H.,Nie, T.,Li, M.,Xu, Y. (deposition date: 2021-11-08, release date: 2022-03-02, Last modification date: 2023-11-29)

Primary citation

Xiong, M.,Nie, T.,Shao, Q.,Li, M.,Su, H.,Xu, Y.
In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease.
Eur.J.Med.Chem., 231:114130-114130, 2022

PubMed Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CL) 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. Moreover, an X-ray crystal structure of the SARS-CoV-2 3CL in complex with compound 8, the most potent hit with an IC 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, but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach.

PubMed: 35114541
DOI: 10.1016/j.ejmech.2022.114130

Experimental method

X-RAY DIFFRACTION (2.51 Å)