A library of novel allosteric inhibitors against fructose 1,6-bisphosphatase

被引：79

作者：

Heng, Sabrina ^{[1
]}

Gryncel, Kimberly R. ^{[1
]}

Kantrowitz, Evan R. ^{[1
]}

机构：

[1] Boston Coll, Dept Chem, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 11期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

Fructose 1,6-bisphosphatase; Type-2; diabetes; ZINC database; Enzyme inhibition; Thiazole derivatives; Virtual high-throughput screening; ACCURATE DOCKING; PROTEIN-PROTEIN; DRUG DISCOVERY; FRUCTOSE-1,6-BISPHOSPHATASE; GLUCONEOGENESIS; 2,6-BISPHOSPHATE; DATABASE; KIDNEY; GLIDE;

D O I：

10.1016/j.bmc.2009.04.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The identification of a proper lead compound for fructose 1,6-bisphosphatase (FBPase) is a critical step in the process of developing novel therapeutics against type-2 diabetes. Herein, we have successfully generated a library of allosteric inhibitors against FBPase as potential anti-diabetic drugs, of which, the lead compound 1b was identified through utilizing a virtual high-throughput screening (vHTS) system, which we have developed. The thiazole-based core structure was synthesized via the condensation of alpha-bromoketones with thioureas and substituents on the two aryl rings were varied. 4c was found to inhibit pig kidney FBPase approximately fivefold better than 1b. In addition, we have also identified 10b, a tight binding fragment, which can be use for fragment-based drug design purposes. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3916 / 3922

页数：7

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