COVID-19 Research Paper Volume 13, Issue 5 pp 6258—6272

Screening potential FDA-approved inhibitors of the SARS-CoV-2 major protease 3CLpro through high-throughput virtual screening and molecular dynamics simulation

Wen-Shan Liu1, *, , Han-Gao Li1, *, , Chuan-Hua Ding1, , Hai-Xia Zhang1, , Rui-Rui Wang3, , Jia-Qiu Li2, ,

  • 1 Shandong Key Laboratory of Clinical Applied Pharmacology, Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong, China
  • 2 Department of Oncology, Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong, China
  • 3 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
* Equal contribution

Received: November 25, 2020       Accepted: February 3, 2021       Published: March 7, 2021
How to Cite

Copyright: © 2021 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


It has been confirmed that the new coronavirus SARS-CoV-2 caused the global pandemic of coronavirus disease 2019 (COVID-19). Studies have found that 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for virus replication, and could be used as a potential target to inhibit SARS-CoV-2. In this work, 3CLpro was used as the target to complete the high-throughput virtual screening of the FDA-approved drugs, and Indinavir and other 10 drugs with high docking scores for 3CLpro were obtained. Studies on the binding pattern of 3CLpro and Indinavir found that Indinavir could form the stable hydrogen bond (H-bond) interactions with the catalytic dyad residues His41-Cys145. Binding free energy study found that Indinavir had high binding affinity with 3CLpro. Subsequently, molecular dynamics simulations were performed on the 3CLpro and 3CLpro-Indinavir systems, respectively. The post-dynamic analyses showed that the conformational state of the 3CLpro-Indinavir system transformed significantly and the system tended to be more stable. Moreover, analyses of the residue interaction network (RIN) and H-bond occupancy revealed that the residue-residue interaction at the catalytic site of 3CLpro was significantly enhanced after binding with Indinavir, which in turn inactivated the protein. In short, through this research, we hope to provide more valuable clues against COVID-19.


3CLpro: 3-chymotrypsin-like protease; COVID-19: Coronavirus Disease 2019; DCCM: dynamic cross-correlation mapping; DS: Discovery Studio; DSSP: definition of secondary structure of proteins; H bond: hydrogen bond; MD: molecular dynamics; MM-PBSA: molecular mechanics Poisson Boltzmann surface area; PCA: principal component analysis; PDB: protein data bank; RINs: residue interaction networks; RMSD: root mean square deviation; RMSF: root mean square fluctuation; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SPC: single-point charge; VDW: Van der Waals.