Discovery of novel inhibitors against main protease (Mpro) of SARS-CoV-2 via virtual screening and biochemical evaluation

Sheng Guo; Hang Xie; Yu Lei; Bin Liu; Li Zhang; Yechun Xu; Zhili Zuo

doi:10.1016/j.bioorg.2021.104767

Discovery of novel inhibitors against main protease (Mpro) of SARS-CoV-2 via virtual screening and biochemical evaluation

Bioorg Chem. 2021 May:110:104767. doi: 10.1016/j.bioorg.2021.104767. Epub 2021 Feb 24.

Authors

Sheng Guo¹, Hang Xie², Yu Lei¹, Bin Liu³, Li Zhang⁴, Yechun Xu⁵, Zhili Zuo⁶

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, 650201, China; School of Chemical Engineering, Sichuan University of Science & Engineering, 180 Xueyuan Street, Huixing Road, Zigong, Sichuan 643000, China.
² CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, 650201, China.
⁴ School of Chemical Engineering, Sichuan University of Science & Engineering, 180 Xueyuan Street, Huixing Road, Zigong, Sichuan 643000, China.
⁵ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zuozhili@mail.kib.ac.cn.
⁶ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, 650201, China. Electronic address: ycxu@simm.ac.cn.

Abstract

SARS-CoV-2 is the pathogen that caused the global COVID-19 outbreak in 2020. Promising progress has been made in developing vaccines and antiviral drugs. Antivirals medicines are necessary complements of vaccines for post-infection treatment. The main protease (Mpro) is an extremely important protease in the reproduction process of coronaviruses which cleaves pp1ab over more than 11 cleavage sites. In this work, two active main protease inhibitors were found via docking-based virtual screening and bioassay. The IC₅₀ of compound VS10 was 0.20 μM, and the IC₅₀ of compound VS12 was 1.89 μM. The finding in this work can be helpful to understand the interactions of main protease and inhibitors. The active candidates could be potential lead compounds for future drug design.

Keywords: Biochemical evaluation; Main protease; SARS-CoV-2; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology*
Coronavirus 3C Proteases / antagonists & inhibitors*
Drug Discovery*
Drug Evaluation, Preclinical
Humans
Molecular Docking Simulation
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
SARS-CoV-2 / enzymology*

Substances

Antiviral Agents
Protease Inhibitors
Coronavirus 3C Proteases