Discovery of potent α-glucosidase inhibitor flavonols: Insights into mechanism of action through inhibition kinetics and docking simulations

Bioorg Chem. 2018 Sep:79:257-264. doi: 10.1016/j.bioorg.2018.05.010. Epub 2018 May 17.

Abstract

Beside other pharmaceutical benefits, flavonoids are known for their potent α-glucosidase inhibition. In the present study, we investigated α-glucosidase inhibitory effects of structurally related 11 flavonols, among which quercetin-3-O-(3″-O-galloyl)-β-galactopyranoside (8) and quercetin 3-O-(6″-O-galloyl)-β-glucopyranoside (9) showed significant inhibition compared to the positive control, acarbose, with IC50 values of 0.97 ± 0.02 and 1.35 ± 0.06 µM, respectively. It was found that while sugar substitution to C3-OH of C ring reduced the α-glucosidase inhibitory effect, galloyl substitution to these sugar units increased it. An enzyme kinetics analysis revealed that 7 was competitive, whereas 1, 2, 8, and 9 were uncompetitive inhibitors. In the light of these findings, we performed molecular docking studies to predict their inhibition mechanisms at atomic level.

Keywords: Enzyme kinetics; Flavonoid; Flavonol; Molecular docking; α-glucosidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Flavonols / chemical synthesis
  • Flavonols / chemistry
  • Flavonols / pharmacology*
  • Glycoside Hydrolase Inhibitors / chemical synthesis
  • Glycoside Hydrolase Inhibitors / chemistry
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Molecular Docking Simulation*
  • Molecular Structure
  • Structure-Activity Relationship
  • alpha-Glucosidases / metabolism*

Substances

  • Flavonols
  • Glycoside Hydrolase Inhibitors
  • alpha-Glucosidases