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

被引：23

作者：

Al-Asri, Jamil ^{[1
]}

Fazekas, Erika ^{[2
]}

Lehoczki, Gabor ^{[2
]}

Perdih, Andrej ^{[3
]}

Goerick, Cornelia ^{[1
]}

Melzig, Matthias F. ^{[1
]}

Gyemant, Gyoengyi ^{[2
]}

Wolber, Gerhard ^{[1
]}

Mortier, Jeremie ^{[1
]}

机构：

[1] Free Univ Berlin, Inst Pharm, Dept Pharmaceut & Med Chem, D-14195 Berlin, Germany

[2] Univ Debrecen, Dept Inorgan & Analyt Chem, H-4032 Debrecen, Hungary

[3] Natl Inst Chem, SI-1001 Ljubljana, Slovenia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 20期

关键词：

alpha-Amylase inhibition; Fragment-based drug design; Virtual screening; Pharmacophore model; Hyperglycaemia; Obesity; Type II diabetes; TYPE-2; DIABETES-MELLITUS; PROTEIN DATA-BANK; ANGSTROM RESOLUTION; STARCH DIGESTION; BINDING; DOCKING; PHARMACOPHORES; DISCOVERY; ENZYMES; ANALOGS;

D O I：

10.1016/j.bmc.2015.09.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Starch catabolism leading to high glucose level in blood is highly problematic in chronic metabolic diseases, such as type II diabetes and obesity. alpha-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 alpha-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 alpha-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 alpha-amylase inhibition. (c) 2015 Elsevier Ltd. All rights reserved.

引用

页码：6725 / 6732

页数：8

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