In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease

Muya Xiong; Tianqing Nie; Qiang Shao; Minjun Li; Haixia Su; Yechun Xu

doi:10.1016/j.ejmech.2022.114130

In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease

Eur J Med Chem. 2022 Mar 5:231:114130. doi: 10.1016/j.ejmech.2022.114130. Epub 2022 Jan 23.

Authors

Muya Xiong¹, Tianqing Nie², Qiang Shao³, Minjun Li⁴, Haixia Su⁵, Yechun Xu⁶

Affiliations

¹ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
³ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China.
⁵ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: suhaixia1@simm.ac.cn.
⁶ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: ycxu@simm.ac.cn.

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 IC₅₀ 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.

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology
COVID-19 Drug Treatment*
Humans
Peptide Hydrolases
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
SARS-CoV-2*

Substances

Antiviral Agents
Protease Inhibitors
Peptide Hydrolases