Molecular basis for drug repurposing to study the interface of the S protein in SARS-CoV-2 and human ACE2 through docking, characterization, and molecular dynamics for natural drug candidates

J Mol Model. 2020 Nov 11;26(12):338. doi: 10.1007/s00894-020-04599-8.


A novel coronavirus (SARS-CoV-2) identified in Wuhan state of China in 2019 is the causative agent of deadly disease COVID-19. It has spread across the globe (more than 210 countries) within a short period. Coronaviruses pose serious health threats to both humans and animals. A recent publication reported an experimental 3D complex structure of the S protein of SARS-CoV-2 showed that the ectodomain of the SARS-CoV-2 S protein binds to the peptidase domain (PD) of human ACE2 with a dissociation constant (Kd) of ~ 15 nM. In this study, we focused on inhibitors for ACE2: S protein complex using virtual screening and inhibition studies through molecular docking for over 200,000 natural compounds. Toxicity analysis was also performed for the best hits, and the final complex structures for four complexes were subjected to 400 ns molecular dynamics simulations for stability testing. We found two natural origin inhibitors for the S protein: human ACE2 complex (Andrographolide and Pterostilbene) which displayed better inhibition potential for ACE2 receptor and its binding with the S protein of SARS-CoV-2. Comparative studies were also performed to test and verify that these two drug candidates are also better than hydroxychloroquine which is known to inhibit this complex. However, we needed better potential drug candidates to overcome the side effects of hydroxychloroquine. Supplementary experimental studies need to be carried forward to corroborate the viability of these two new inhibitors for ACE2: S protein complex so as to curb down COVID-19.

Keywords: Andrographolide; COVID-19; Molecular dynamics; S protein: human ACE2 complex; SARS-CoV-2.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Betacoronavirus / genetics
  • Betacoronavirus / physiology*
  • COVID-19
  • Coronavirus Infections / epidemiology*
  • Coronavirus Infections / virology
  • Drug Repositioning
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Pandemics
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism*
  • Pneumonia, Viral / epidemiology*
  • Pneumonia, Viral / virology
  • Protein Domains
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism*


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptide Hydrolases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2