Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease

Molecules. 2020 Nov 6;25(21):5172. doi: 10.3390/molecules25215172.


Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure-Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (Mpro) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the Mpro of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the Mpro enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.

Keywords: COVID-19; QSAR; SARS-CoV-2; drugs repurposing; molecular dynamics.

MeSH terms

  • Amobarbital / pharmacology
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Binding Sites
  • COVID-19 Drug Treatment*
  • Computer Simulation
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Drug Discovery / methods*
  • Drug Repositioning / methods*
  • Humans
  • Machine Learning
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Pandemics
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / enzymology*
  • Small Molecule Libraries / chemistry
  • Software
  • Thermodynamics
  • Thyroxine / pharmacology


  • Antiviral Agents
  • Protease Inhibitors
  • Small Molecule Libraries
  • 3C-like protease, SARS coronavirus
  • Coronavirus 3C Proteases
  • Amobarbital
  • Thyroxine