Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands
Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands
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DOI：
10.1021/jm0005353
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发表时间：
2001-05-24
影响因子：
7.3
通讯作者：
Miller, DD
中科院分区：
文献类型：
--
作者：
Marhefka, CA;Moore, BM II;Miller, DD
为了促进新的和更有效的雄激素受体配体的合理设计，人类雄激素受体配体结合域与睾酮结合的三维模型已经被开发出来。这些雄激素受体的模型是基于高度同源的人黄体酮受体配体结合域的晶体结构。在显性溶剂中，通过不受约束的多分子动力学模拟，完善了雄激素受体的同源性模型，与睾酮的17-羟基和3-酮基的关键氢键伙伴分别是Asn705和Thr877， Gln711和Arg752。这些模型显示雄激素受体结合袋内存在一个独特的空腔，这可能对开发新的选择性雄激素受体配体有价值。对hAR结合袋内氨基酸突变影响配体结合的定性分析与这些雄激素受体模型一致。除了睾酮外，还研究了几种羟氟烷类非甾体配体与雄激素受体的结合模式，使用flexxx进行灵活对接，然后通过分子动力学模拟对初始复合物进行改进。这些对接研究表明，Asn705通过参与与这些配体的a-羟基部分的ii键相互作用，是结合羟氟他胺及其衍生物的重要决定因素。此外，硝基功能模仿天然配体睾酮的3-酮基团，并参与与Gln711和Arg752的ii键相互作用。从这些对接研究中，我们提出了手性羟氟他胺衍生物对映选择性结合的机制，并扩展了先前报道的羟氟他胺及其衍生物的构效关系。
To facilitate the rational design of novel and more potent androgen receptor ligands, three-dimensional models for the human androgen receptor ligand binding domain bound to testosterone have been developed. These models of the androgen receptor were based on the crystal structure of the highly homologous human progesterone receptor ligand binding domain. The homology modeled androgen receptor was refined using unrestrained multiple molecular dynamics simulations in explicit solvent, Key H-bonding partners with the 17-hydroxy group and 3-keto group of testosterone are Asn705 and Thr877, and Gln711 and Arg752, respectively. These models show the presence of a unique unoccupied cavity within the androgen receptor binding pocket which may be valuable in the development of novel selective androgen receptor ligands. A qualitative analysis of amino acid mutations within the hAR binding pocket that affect ligand binding are consistent with these androgen receptor models. In addition to testosterone, the binding modes of several hydroxyflutamide-like nonsteroidal ligands for the androgen receptor are investigated using flexible docking with FlexX followed by refinement of the initial complexes with molecular dynamics simulations. These docking studies indicate that Asn705 is an important determinant in binding hydroxyflutamide and its derivatives by participating in II-bond interactions with the a-hydroxy moiety of these ligands. In addition, the nitro functionality mimics the 3-keto group of the natural ligand testosterone and is involved in II-bonding interactions with Gln711 and Arg752. From these docking studies, we suggest a mechanism for the enantioselective binding of chiral hydroxyflutamide derivatives and expand upon the previously reported structure-activity relationship for hydroxyflutamide and its derivatives.