From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors

Jamil Al-Asri, Erika Fazekas, Gábor Lehoczki, Andrej Perdih, Cornelia Görick, Matthias F. Melzig, Gyöngyi Gyémánt, Gerhard Wolber, Jérémie Mortier

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11 Citations (Scopus)

Abstract

Starch catabolism leading to high glucose level in blood is highly problematic in chronic metabolic diseases, such as type II diabetes and obesity. α-Amylase catalyzes the hydrolysis of starch, increasing blood sugar concentration. Its inhibition represents a promising therapeutic approach to control hyperglycaemia. However, only few drug-like molecule inhibitors without sugar moieties have been discovered so far, and little information on the enzymatic mechanism is available. This work aims at the discovery of novel small α-amylase binders using a systematic in silico methodology. 3D-pharmacophore-based high throughput virtual screening of small compounds libraries was performed to identify compounds with high α-amylase affinity. Twenty-seven compounds were selected and biologically tested, revealing IC50 values in the micromolar range and ligand efficiency higher than the one of the bound form of acarbose, which is used as a reference for α-amylase inhibition.

Original languageEnglish
Pages (from-to)6725-6732
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number20
DOIs
Publication statusPublished - Oct 15 2015

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Keywords

  • Fragment-based drug design
  • Hyperglycaemia
  • Obesity
  • Pharmacophore model
  • Type II diabetes
  • Virtual screening
  • α-Amylase inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Al-Asri, J., Fazekas, E., Lehoczki, G., Perdih, A., Görick, C., Melzig, M. F., Gyémánt, G., Wolber, G., & Mortier, J. (2015). From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors. Bioorganic and Medicinal Chemistry, 23(20), 6725-6732. https://doi.org/10.1016/j.bmc.2015.09.007