Identification of small molecule estrogen-related receptor α-specific antagonists and homology modeling to predict the molecular determinants as the basis for selectivity over ERRβ and ERRγ
Identification of small molecule estrogen-related receptor α-specific antagonists and homology modeling to predict the molecular determinants as the basis for selectivity over ERRβ and ERRγ
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DOI：
10.1002/ddr.20246
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发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Wilkinson, Hilary A.
中科院分区：
文献类型：
--
作者：
Chisamore, Michael J.;Mosley, Ralph T.;Wilkinson, Hilary A.
雌激素相关受体（ERR α）是通过寻找与类固醇核受体雌激素受体（ER α）相关的蛋白编码基因而发现的首批孤儿受体之一。ERR α的生理作用尚未确定，自然配体也未被阐明。重要的是，研究表明ERR α可能是治疗乳腺癌和/或代谢紊乱的新药物靶点。一种均匀的时间分辨荧光（HTRF）测定方法已经开发出来，用于筛选ERR α特异性拮抗剂。该试验使用增殖激活受体γ共激活因子-1 α (PGC-1 α)的ERR配体结合域和辅激活因子相互作用域来检测化合物拮抗ERR α和辅激活因子之间组成性相互作用的能力。还创建了解离增强镧系元素荧光免疫分析法（DELFIA）来对抗在htfr筛选中鉴定的筛选化合物。在这里，我们报告了高亲和力ERR α亚型选择性拮抗剂的发现。此外，在拮抗剂构象中的ERRa的同源性模型已经开发出来，在随后的对接研究之后，我们提供了一个模型，显示了分子决定因素，说明为什么我们的新型三环拮抗剂N-[(2Z)-3-（4,5-二氢-1,3-噻唑-2-基）-1,3-噻唑烷-2-基]-5 H二苯并[a，d][7]环-5胺，高亲和力地与ERR α结合，但不与ERR β或ERR γ结合。医药工程学报（英文版），2008。(C) 2008 Wiley-Liss, Inc。
The estrogen-related receptor alpha (ERR alpha) was one of the first orphan receptors identified through a search for genes encoding proteins related to the steroid nuclear receptor, Estrogen Receptor alpha (ER alpha). The physiological role of ERR alpha has not yet been established nor has a natural ligand been elucidated. Importantly, research indicates that ERR alpha may be a novel drug target to treat breast cancer and/or metabolic disorders. A homogeneous time-resolved fluorescence (HTRF) assay has been developed to screen for ERR alpha-specific antagonists. This assay uses the ERR ligand binding domain and the coactivator interaction domain of Proliferator-activated Receptor gamma Coactivator-1 alpha (PGC-1 alpha) to examine the ability of compounds to antagonize the constitutive interaction between ERR alpha and the coactivator. A dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) was also created to counter screen compounds identified in the HTRF screen. Here we report the discovery of high-affinity ERR alpha subtype selective antagonists. Additionally, a homology model of ERRa in an antagonist conformation has been developed and after subsequent docking studies, we offer a model showing the molecular determinants that suggest why our novel tri-cyclic antagonist, N-[(2Z)-3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-yl idene]-5 H dibenzo[a,d] [7]annulen-5-amine, binds to ERR alpha with high affinity but does not bind to either ERR beta or ERR gamma. Drug Dev Res 69:203-218, 2008. (C) 2008 Wiley-Liss, Inc.