COVID19-inhibitory activity of withanolides involves targeting of the host cell surface receptor ACE2: insights from computational and biochemical assays

J Biomol Struct Dyn. 2022 Oct;40(17):7885-7898. doi: 10.1080/07391102.2021.1902858. Epub 2021 Apr 2.


SARS-CoV-2 outbreak in China in December 2019 and its spread as worldwide pandemic has been a major global health crisis. Extremely high infection and mortality rate has severely affected all sectors of life and derailed the global economy. While drug and vaccine development have been prioritized and have made significant progression, use of phytochemicals and herbal constituents is deemed as a low-cost, safer and readily available alternative. We investigated therapeutic efficacy of eight withanolides (derived from Ashwagandha) against the angiotensin-converting enzyme 2 (ACE2) proteins, a target cell surface receptor for SARS-CoV-2 and report results on the (i) computational analyses including binding affinity and stable interactions with ACE2, occupancy of ACE2 residues in making polar and nonpolar interactions with different withanolides/ligands and (2) in vitro mRNA and protein analyses using human cancer (A549, MCF7 and HSC3) cells. We found that among all withanolides, Withaferin-A, Withanone, Withanoside-IV and Withanoside-V significantly inhibited the ACE2 expression. Analysis of withanolides-rich aqueous extracts derived from Ashwagandha leaves and stem showed a higher ACE2 inhibitory potency of stem-derived extracts. Taken together, we demonstrated the inhibitory potency of Ashwagandha withanolides and its aqueous extracts against ACE2.Communicated by Ramaswamy H. Sarma.

Keywords: inhibition; Ashwagandha; COVID-19; Coronavirus; SARS-CoV-2; Withania somnifera; angiotensin-converting enzyme 2; withanolides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • COVID-19 Drug Treatment*
  • Humans
  • Ligands
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / metabolism
  • SARS-CoV-2
  • Withania* / chemistry
  • Withania* / metabolism
  • Withanolides* / chemistry
  • Withanolides* / metabolism
  • Withanolides* / pharmacology


  • Ligands
  • RNA, Messenger
  • Receptors, Cell Surface
  • Withanolides
  • Angiotensin-Converting Enzyme 2

Grants and funding

This study was supported by the funds granted by AIST (Japan) and DBT (Government of India).