Evolutionary chemistry approach toward finding novel inhibitors of the type 2 diabetes target glucose-6-phosphate translocase

被引：30

作者：

Bräuer, S ^{[1
]}

Almstetter, M ^{[1
]}

Antuch, W ^{[1
]}

Behnke, D ^{[1
]}

Taube, R ^{[1
]}

Furer, P ^{[1
]}

Hess, S ^{[1
]}

机构：

[1] Morphochem AG, D-81379 Munich, Germany

来源：

JOURNAL OF COMBINATORIAL CHEMISTRY | 2005年 / 7卷 / 02期

关键词：

D O I：

10.1021/cc049867

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

A genetic algorithm (GA), driven by experimentally determined biological activities as a feedback fitness function, was used to propose novel small molecules as inhibitors of glucose-6-phosphate translocase (G6PT) in iterative rounds of evolutionary optimization. A straightforward polymer-supported synthetic sequence was implemented to synthesize molecules proposed by the GA, and the biological activities of the compounds were determined by a microsomal assay. Additional compound design strategies were integrated, such as Tanimoto similarity-based selection of starting materials and transfer of favored structure elements into a new chemical scaffold to identify more active and selective inhibitors.

引用

页码：218 / 226

页数：9

共 42 条

[1] Direct evidence for the involvement of two glucose 6-phosphate-binding sites in the glucose-6-phosphatase activity of intact liver microsomes - Characterization of T1, the microsomal glucose 6-phosphate transport protein by a direct binding assay [J].