Identification of small-molecule inhibitors of the steroidogenic acute regulatory protein (STARD1) by structure-based design

被引：14

作者：

Akula, Nagaraju ^{[1
]}

Midzak, Andrew ^{[1
,2
]}

Lecanu, Laurent ^{[1
,2
]}

Papadopoulos, Vassilios ^{[1
,2
]}

机构：

[1] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ H3G 1A4, Canada

[2] McGill Univ, Dept Med, Montreal, PQ H3G 1A4, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 12期

基金：

加拿大健康研究院;

关键词：

STAR; Steroiodogenesis; Cholesterol; Leydig cells; CHOLESTEROL; DOMAIN; BIOSYNTHESIS; TRANSPORT; DOCKING; MODELER;

D O I：

10.1016/j.bmcl.2012.04.058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A homology model of the steroidogenic acute regulatory protein (STAR)-related lipid transfer (START) domain of STARD1 was built, and the cholesterol binding site was identified. Structure-based design studies were performed to identify small molecule inhibitors of the START domain. The lead compounds were selected based on cAMP-induced, but not 22R-hydroxycholesterol-supported, inhibition of steroid synthesis by 50% at 10 mu M. The results obtained by molecular docking & dynamics show a good correlation between bioactivity, docking scores and calculated binding energies of ligand-protein complexes. The best active compounds will be optimized further and used to develop potential drugs to control excessive steroid formation. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：4139 / 4143

页数：5

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