An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

Sci Rep. 2020 Aug 17;10(1):13866. doi: 10.1038/s41598-020-70863-9.

Abstract

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Angiotensin-Converting Enzyme 2
  • Benzodioxoles / pharmacology
  • Betacoronavirus / chemistry
  • Betacoronavirus / drug effects*
  • Binding Sites
  • COVID-19
  • Computational Biology / methods*
  • Coronavirus Infections / metabolism*
  • Coronavirus Infections / virology
  • Drug Discovery / methods*
  • Drug Repositioning / methods*
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Pandemics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / virology
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Domains / drug effects
  • Protein Interaction Maps / drug effects
  • SARS-CoV-2
  • Simeprevir / pharmacology
  • Spike Glycoprotein, Coronavirus / antagonists & inhibitors
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Aminopyridines
  • Benzodioxoles
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Simeprevir
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • lumacaftor