Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 coronavirus

J Biomol Struct Dyn. 2022 Feb;40(3):1331-1346. doi: 10.1080/07391102.2020.1828172. Epub 2020 Oct 4.


SARS-CoV-2, an emerging coronavirus, has spread rapidly around the world, resulting in over ten million cases and more than half a million deaths as of July 1, 2020. Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Previous studies demonstrated that nonstructural protein 16 (nsp16) of coronavirus is an S-adenosyl methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that has an important role in viral replication and prevents recognition by the host innate immune system. In the present study, we employed structural analysis, virtual screening, and molecular simulation approaches to identify clinically investigated and approved drugs which can act as promising inhibitors against nsp16 2'-O-MTase of SARS-CoV-2. Comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs defined the key residues for nsp16 2-O'-MTase functions. Virtual screening and docking analysis ranked the potential inhibitors of nsp16 from more than 4,500 clinically investigated and approved drugs. Furthermore, molecular dynamics simulations were carried out on eight top candidates, including Hesperidin, Rimegepant, Gs-9667, and Sonedenoson, to calculate various structural parameters and understand the dynamic behavior of the drug-protein complexes. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and/or clinically for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

Keywords: KDKE motif; SARS-CoV-2; inhibitor; methyltransferase; molecular dynamics simulation; nsp16; virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 Drug Treatment*
  • COVID-19 Vaccines
  • Humans
  • Methyltransferases
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Ribose
  • SARS-CoV-2*


  • COVID-19 Vaccines
  • Ribose
  • Methyltransferases

Grants and funding

This work was partially supported by grants from the Department of Defense (DoD) Breast Cancer Program BC161536, Elsa U. Pardee Foundation, DMC Foundation and Molecular Therapeutics Program of Karmanos Cancer Institute to Dr. Zeng-Quan Yang; and by funding from Susan G. Komen GTDR14299438 and Wayne State University Graduate School Dean Mathur Fellowship to Morenci Manning.