Feasibility of the inhibitor development for SARS-CoV-2: a systematic approach for drug design

Guangzhou Sun; Quanshan Shi; Yuting Song; Dazhi Cheng; Yu Jiang; Dongling Hu; Xinru Yue; Wentong Yu; Xiaodong Shi; Jianping Hu

doi:10.1007/s00894-025-06541-2

Feasibility of the inhibitor development for SARS-CoV-2: a systematic approach for drug design

J Mol Model. 2025 Nov 28;31(12):352. doi: 10.1007/s00894-025-06541-2.

Authors

Guangzhou Sun^#¹, Quanshan Shi^#¹, Yuting Song², Dazhi Cheng¹, Yu Jiang¹, Dongling Hu¹, Xinru Yue¹, Wentong Yu¹, Xiaodong Shi³, Jianping Hu⁴

Affiliations

¹ Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China.
² Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
³ Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China. shixiaodong@cdu.edu.cn.
⁴ Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China. hjpcdu@163.com.

^# Contributed equally.

PMID: 41313484
DOI: 10.1007/s00894-025-06541-2

Abstract

Context: The main protease (M^pro) of SARS-CoV-2 is highly conserved with low variability. It plays a key role in viral replication, making it a target for COVID-19 treatment. Currently, drugs like Paxlovid have significant side effects and high costs, so new alternatives are urgently needed.

Methods: In this work, a medicine and food homology herbal drugs (MF-HHD) database is constructed, followed by a multi-scale and high-precision screening with various virtual screening techniques (ligand-based pharmacophore screening, Vina-based screening, and drug-forming, prescription-based screening). Quercetin was identified as a potent M^pro inhibitor through multi-stage virtual screening. Molecular dynamics simulations (500 ns) revealed its binding mechanism and stabilization effects on M^pro. The results revealed that upon binding, the inhibitor interacted with H41, H164, M165, L167, P168, D187, R188, Q189, and Q192 and altered the hydrogen bonding network between M^pro and the solvent allowing the inhibitor to bind the active pocket. Free energy landscape (FEL) and conformational clustering analysis showed that M^pro undergoes significant conformational changes when bound to quercetin. In this way, a complete drug screening chain will be used to search for potential M^pro inhibitors and obtain computationally validated candidate that can for experimental evaluation COVID-19.

Keywords: Drug screening; Hydrogen-bond network; Main protein; Medicine and food homology herbal drugs database; SARS-CoV-2.

MeSH terms

Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
COVID-19 / virology
COVID-19 Drug Treatment*
Coronavirus 3C Proteases* / antagonists & inhibitors
Coronavirus 3C Proteases* / chemistry
Coronavirus 3C Proteases* / metabolism
Drug Design*
Feasibility Studies
Humans
Hydrogen Bonding
Molecular Docking Simulation
Molecular Dynamics Simulation
Protease Inhibitors* / chemistry
Protease Inhibitors* / pharmacology
Protein Binding
Quercetin / chemistry
Quercetin / pharmacology
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology

Substances

Coronavirus 3C Proteases
Quercetin
Antiviral Agents
Protease Inhibitors