Discovery of potent α-glucosidase inhibitors through structure-based virtual screening of an in-house azole collection

Chem Biol Drug Des. 2021 Mar;97(3):701-710. doi: 10.1111/cbdd.13805. Epub 2020 Nov 5.

Abstract

Diabetes mellitus, a chronic disorder characterized by hyperglycemia, is considered a pandemic of modern times. α-Glucosidase inhibitors emerged as a promising class of antidiabetic drugs with better tolerability compared with its alternatives. Azoles, although widely preferred in drug design, have scarcely been investigated for their potential against α-glucosidase. In this study, we evaluated α-glucosidase inhibitory effects 20 azole derivatives selected out of an in-house collection via structure-based virtual screening (VS) with consensus scoring approach. Seven compounds were identified with better IC50 values than acarbose (IC50 = 68.18 ± 1.01 µM), a well-known α-glucosidase inhibitor drug, which meant 35% success for our VS methodology. Compound 52, 54, 56, 59, and 81 proved highly potent with IC50 values in the range of 40-60 µM. According to the enzyme kinetics study, four of them were competitive, 56 was non-competitive inhibitor. Structure-activity relationships, quantum mechanical, and docking analyses showed that azole rings at ionized state may be key to the potency observed for the active compounds and modifications to shift the balance between the neutral and ionized states further to the latter could yield more potent derivatives.

Keywords: azole; consensus scoring; enzyme kinetics; pKa prediction; virtual screening; α-glucosidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azoles / chemistry*
  • Azoles / metabolism
  • Azoles / therapeutic use
  • Binding Sites
  • Binding, Competitive
  • Databases, Chemical
  • Diabetes Mellitus, Type 2 / drug therapy
  • Glycoside Hydrolase Inhibitors / chemistry*
  • Glycoside Hydrolase Inhibitors / metabolism
  • Glycoside Hydrolase Inhibitors / therapeutic use
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Quantum Theory
  • Structure-Activity Relationship
  • alpha-Glucosidases / chemistry*
  • alpha-Glucosidases / metabolism

Substances

  • Azoles
  • Glycoside Hydrolase Inhibitors
  • alpha-Glucosidases