Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs.
Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs.
复制标题
灵活的 GBR 12909 二烷基哌嗪和哌啶类似物的层次聚类分析。
DOI：
10.1007/s10822-006-9046-2
复制
发表时间：
2006
影响因子：
3.5
通讯作者：
Venanzi,CarolA
中科院分区：
文献类型：
--
作者：
Gilbert,KathleenM;Venanzi,CarolA
像多巴胺再摄取抑制剂GBR 12909这样的大型药物样分子的药效团建模由于其灵活性而变得复杂。对两种GBR 12909类似物进行了全面的分层聚类研究，以确定具有代表性的构象，为密切相关类似物的三维定量构效关系研究提供输入。研究了哌嗪和哌啶GBR 12909类似物随机搜索产生的700多个构象的两个数据集。基于包含重要药效团元素的不同特征集进行了几种聚类研究。距离图，有效簇数相对于实际簇数的图，以及新导出的聚类统计量，有效簇数的百分比变化，在确定适当的聚类水平时是有用的。每个模拟物选择了六个簇，每个簇代表一个不同的扭转角空间区域，该区域决定药效团元素的相对方向。每个集群的构象是这些地区的代表，确定和比较每个模拟。这项研究说明了在关键药效团元素的三维空间取向方面使用分层聚类对高柔性分子构象进行分类的效用。
Pharmacophore modeling of large, drug-like molecules, such as the dopamine reuptake inhibitor GBR 12909, is complicated by their flexibility. A comprehensive hierarchical clustering study of two GBR 12909 analogs was performed to identify representative conformers for input to three-dimensional quantitative structure–activity relationship studies of closely-related analogs. Two data sets of more than 700 conformers each produced by random search conformational analysis of a piperazine and a piperidine GBR 12909 analog were studied. Several clustering studies were carried out based on different feature sets that include the important pharmacophore elements. The distance maps, the plot of the effective number of clusters versus actual number of clusters, and the novel derived clustering statistic, percentage change in the effective number of clusters, were shown to be useful in determining the appropriate clustering level.Six clusters were chosen for each analog, each representing a different region of the torsional angle space that determines the relative orientation of the pharmacophore elements. Conformers of each cluster that are representative of these regions were identified and compared for each analog. This study illustrates the utility of using hierarchical clustering for the classification of conformers of highly flexible molecules in terms of the three-dimensional spatial orientation of key pharmacophore elements.