A library of novel allosteric inhibitors against fructose 1,6-bisphosphatase
详细信息 查看全文
- 作者：Sabrina Heng ; Kimberly R. Gryncel ; Evan R. Kantrowitz
- 关键词：Fructose 1 ; 6-bisphosphatase ; Type-2 diabetes ; ZINC database ; Enzyme inhibition ; Thiazole derivatives ; Virtual high-throughput screening
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2009
- 出版时间：1 June 2009
- 年：2009
- 卷：17
- 期：11
- 页码：3916-3922
- 全文大小：271 K
文摘
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 α-bromo-ketones 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.