期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 17, 期 11, 页码 3916-3922出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.04.030
关键词
Fructose 1,6-bisphosphatase; Type-2 diabetes; ZINC database; Enzyme inhibition; Thiazole derivatives; Virtual high-throughput screening
资金
- National Institutes of Health [GM26237]
- National Science Foundation
- Boston College Mass Spectrometry Center [DBI-0619576]
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.
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