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

doi:10.1016/j.bmc.2015.09.007

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

Bioorg Med Chem. 2015 Oct 15;23(20):6725-32. doi: 10.1016/j.bmc.2015.09.007. Epub 2015 Sep 8.

Authors

Jamil Al-Asri¹, Erika Fazekas², Gábor Lehoczki², Andrej Perdih³, Cornelia Görick¹, Matthias F Melzig¹, Gyöngyi Gyémánt², Gerhard Wolber⁴, Jérémie Mortier⁵

Affiliations

¹ Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany.
² University of Debrecen, Department of Inorganic & Analytical Chemistry, Egyetem ter 1, PO Box 21, H-4032 Debrecen, Hungary.
³ National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
⁴ Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany. Electronic address: gerhard.wolber@fu-berlin.de.
⁵ Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutical & Medicinal Chemistry, Königin-Luise Str. 2-4, 14195 Berlin, Germany. Electronic address: jeremie.mortier@fu-berlin.de.

PMID: 26395057
DOI: 10.1016/j.bmc.2015.09.007

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.

Keywords: Fragment-based drug design; Hyperglycaemia; Obesity; Pharmacophore model; Type II diabetes; Virtual screening; α-Amylase inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbohydrates / chemistry
Carbohydrates / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
High-Throughput Screening Assays
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
alpha-Amylases / antagonists & inhibitors*
alpha-Amylases / metabolism

Substances

Carbohydrates
Enzyme Inhibitors
alpha-Amylases