Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study

J Chem Inf Model. 2020 Jun 22;60(6):3277-3286. doi: 10.1021/acs.jcim.0c00179. Epub 2020 May 4.


The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson-Boltzmann surface area/weighted solvent-accessible surface area; Wang, Chem. Rev. 2019, 119, 9478; Wang, Curr. Comput.-Aided Drug Des. 2006, 2, 287; Wang; ; Hou J. Chem. Inf. Model., 2012, 52, 1199). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Betacoronavirus / chemistry
  • Betacoronavirus / drug effects*
  • Betacoronavirus / enzymology
  • COVID-19
  • Coronavirus 3C Proteases
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Drug Repositioning / economics
  • Drug Repositioning / methods*
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • SARS-CoV-2
  • Tetracyclines / chemistry
  • Tetracyclines / pharmacology
  • Thermodynamics
  • Time Factors
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism


  • Anti-Bacterial Agents
  • Oligopeptides
  • Protease Inhibitors
  • Tetracyclines
  • Viral Nonstructural Proteins
  • eravacycline
  • carfilzomib
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases