In Silico Characterization of Masitinib Interaction with SARS-CoV-2 Main Protease

ChemMedChem. 2021 Aug 5;16(15):2339-2344. doi: 10.1002/cmdc.202100375. Epub 2021 Jul 9.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a global health problem. Despite the current implementation of COVID-19 vaccination schedules, identifying effective antiviral drug treatments for this disease continues to be a priority. A recent study showed that masitinib (MST), a tyrosine kinase inhibitor, blocks the proteolytic activity of SARS-CoV-2 main protease (Mpro ). Although MST is a potential candidate for COVID-19 treatment, a comprehensive analysis of its interaction with Mpro has not been done. In this work, we performed molecular dynamics simulations of the MST-Mpro complex crystal structure. The effect of the protonation states of Mpro H163 residue and MST titratable groups were studied. Furthermore, we identified the MST substituents and Mpro mutations that affect the stability of the complex. Our results provide valuable insights into the design of new MST analogs as potential treatments for COVID-19.

Keywords: Main protease; Masitinib; Molecular dynamics; Protonation states; SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides
  • Catalytic Domain
  • Coronavirus 3C Proteases / antagonists & inhibitors
  • Coronavirus 3C Proteases / chemistry
  • Coronavirus 3C Proteases / genetics
  • Coronavirus 3C Proteases / metabolism*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / metabolism*
  • Hydrogen Bonding
  • Molecular Dynamics Simulation
  • Mutation
  • Piperidines
  • Protein Binding
  • Pyridines
  • SARS-CoV-2 / enzymology*
  • Static Electricity
  • Thiazoles / chemistry
  • Thiazoles / metabolism*

Substances

  • Benzamides
  • Cysteine Proteinase Inhibitors
  • Piperidines
  • Pyridines
  • Thiazoles
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases
  • masitinib