Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors

Chem Biol Drug Des. 2019 Dec;94(6):2023-2030. doi: 10.1111/cbdd.13604. Epub 2019 Sep 12.


Middle East respiratory syndrome-coronavirus (MERS-CoV) is a zoonotic virus transmitted between animals and human beings. It causes MERS with high mortality rate. However, no vaccine or specific treatment is currently available. Since antiviral activity of some flavonoids is known, we applied a flavonoid library to probe inhibitory compounds against MERS-CoV 3C-like protease (3CLpro). Herbacetin, isobavachalcone, quercetin 3-β-d-glucoside and helichrysetin were found to block the enzymatic activity of MERS-CoV 3CLpro. The binding of the four flavonoids was also confirmed independently using a tryptophan-based fluorescence method. The systematic comparison of the binding affinity of flavonoids made it possible to infer their scaffolds and functional groups required to bind with MERS-CoV 3CLpro. An induced-fit docking analysis revealed that S1 and S2 sites play a role in interaction with flavonoids. The experimental and computational study showed that flavonol and chalcone are favourite scaffolds to bind with the catalytic site of MERS-CoV 3CLpro. It was also deduced that some flavonoid derivatives with hydrophobic or carbohydrate attached to their core structures have a good inhibitory effect. Therefore, we suggest that flavonoids with these characteristics can be used as templates to develop potent MERS-CoV 3CLpro inhibitors.

Keywords: FRET; MERS-CoV; MERS-CoV 3CLpro; flavonoid; inhibitory compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Binding Sites
  • Flavonoids / chemistry*
  • Flavonoids / metabolism
  • Glucosides / chemistry
  • Glucosides / metabolism
  • Humans
  • Middle East Respiratory Syndrome Coronavirus / enzymology*
  • Molecular Docking Simulation
  • Peptide Hydrolases / chemistry*
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Quercetin / analogs & derivatives
  • Quercetin / chemistry
  • Quercetin / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism


  • Antiviral Agents
  • Flavonoids
  • Glucosides
  • Protease Inhibitors
  • Recombinant Proteins
  • Viral Proteins
  • quercetin 3'-O-glucoside
  • Quercetin
  • Peptide Hydrolases