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

SARI S., Barut B., ÖZEL A., Sarac S.

CHEMICAL BIOLOGY & DRUG DESIGN, vol.97, no.3, pp.701-710, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 97 Issue: 3
  • Publication Date: 2021
  • Doi Number: 10.1111/cbdd.13805
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.701-710
  • Keywords: azole, consensus scoring, enzyme kinetics, pKa prediction, virtual screening, &#945, &#8208, glucosidase, MECHANISTIC INSIGHTS, DRUG DISCOVERY, DOCKING, KINETICS, VITRO, DERIVATIVES, PERFORMANCE, FLAVONOIDS, PROTEIN, GLIDE
  • Karadeniz Technical University Affiliated: Yes


Diabetes mellitus, a chronic disorder characterized by hyperglycemia, is considered a pandemic of modern times. alpha-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 alpha-glucosidase. In this study, we evaluated alpha-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 mu M), a well-known alpha-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 mu M. 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.