Molecular Modeling on Inhibitor Complexes and Active-Site Dynamics of Cytochrome P450 C17, a Target for Prostate Cancer Therapy
Molecular Modeling on Inhibitor Complexes and Active-Site Dynamics of Cytochrome P450 C17, a Target for Prostate Cancer Therapy
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DOI：
10.1016/j.jmb.2010.05.069
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发表时间：
2010-07-30
影响因子：
5.6
通讯作者：
Neidle, Stephen
中科院分区：
文献类型：
--
作者：
Haider, Shozeb M.;Patel, Jagdish S.;Neidle, Stephen
P450酶细胞色素P450 C17（CYP17）的分子模型根据多个模板结构和同源性建模的序列比对提出。该酶在睾丸激素的生物合成中起着核心作用，并且正在成为前列腺癌的主要靶标，而最近开发的抑制剂阿比罗酮目前正在晚期临床试验中。该模型通过为可用地点定向的诱变数据提供结构解释详细描述了该模型。该模型中的CYP17分子的形式为三角形的棱镜，其边缘与55埃埃斯特罗姆（Angstrom）相似，厚度类似于37埃斯特罗姆（Angstrom）。它主要是螺旋，包括13个α螺旋，散布在6（10）个螺旋螺旋和11个β片。已经进行了显式溶剂中的多动秒分子动力学模拟，并且主要成分分析已用于揭示活动位点周围动力学的细节。粗粒方法也已用于验证与活动位点门控相关的低频运动。这项工作还描述了CYP17活性位点中对接合成抑制剂的结果，包括阿比里特酮和天然底物妊娠，以及复合物上的分子动力学模拟。 （c）2010 Elsevier Ltd.保留所有权利。
A molecular model for the P450 enzyme cytochrome P450 C17 (CYP17) is presented based on sequence alignments of multiple template structures and homology modeling. This enzyme plays a central role in the biosynthesis of testosterone and is emerging as a major target in prostate cancer, with the recently developed inhibitor abiraterone currently in advanced clinical trials. The model is described in detail, together with its validation, by providing structural explanations to available site-directed mutagenesis data. The CYP17 molecule in this model is in the form of a triangular prism, with an edge of similar to 55 angstrom and a thickness of similar to 37 angstrom. It is predominantly helical, comprising 13 alpha helices interspersed by six 3(10) helices and 11 beta-sheets. Multinanosecond molecular dynamics simulations in explicit solvent have been carried out, and principal components analysis has been used to reveal the details of dynamics around the active site. Coarse-grained methods have also been used to verify low-frequency motions, which have been correlated with active-site gating. The work also describes the results of docking synthetic inhibitors, including the drug abiraterone and the natural substrate pregnenolone, in the CYP17 active site together with molecular dynamics simulations on the complexes. (C) 2010 Elsevier Ltd. All rights reserved.