A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor
A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor
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DOI：
10.1021/jm0499007
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发表时间：
2004-07-15
影响因子：
7.3
通讯作者：
Dalton, JT
中科院分区：
文献类型：
--
作者：
Bohl, CE;Chang, C;Dalton, JT
利用比较分子场分析（CoMFA）技术，研究了一类内源性和合成雄激素受体（AR）化合物的三维定量构效关系（QSAR）。这些研究的目的是确定高结合亲和力和优化选择性雄激素受体调节剂（SARMs）所需的结构特征。在CoMFA建模之前，AR的同源性模型被用作支架来排列6个先导化合物，这些先导化合物作为模板用于其余116个结构的排列。与观测值和预测值相关的常规r(2)和交叉验证q(2)分别为0.949和0.593。对10个化合物的测试集进行预测RBA与观测RBA比较，r(2)为0.954，表明该模型具有良好的预测能力。这些整合的同源性建模和CoMFA研究确定了SARM相互作用的关键氨基酸，并提供了QSAR数据，作为AR结构、功能和优化SARM设计的机制研究的基础。
We examined the three-dimensional quantitative structure-activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r(2) and cross-validated q(2) relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r(2) of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs.