Drwal Malgorzata N, Agama Keli, Pommier Yves, Griffith Renate
Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
J Comput Aided Mol Des. 2013 Dec;27(12):1037-49. doi: 10.1007/s10822-013-9695-x. Epub 2013 Dec 1.
Purely structure-based pharmacophores (SBPs) are an alternative method to ligand-based approaches and have the advantage of describing the entire interaction capability of a binding pocket. Here, we present the development of SBPs for topoisomerase I, an anticancer target with an unusual ligand binding pocket consisting of protein and DNA atoms. Different approaches to cluster and select pharmacophore features are investigated, including hierarchical clustering and energy calculations. In addition, the performance of SBPs is evaluated retrospectively and compared to the performance of ligand- and complex-based pharmacophores. SBPs emerge as a valid method in virtual screening and a complementary approach to ligand-focussed methods. The study further reveals that the choice of pharmacophore feature clustering and selection methods has a large impact on the virtual screening hit lists. A prospective application of the SBPs in virtual screening reveals that they can be used successfully to identify novel topoisomerase inhibitors.
基于结构的纯药效团（SBPs）是基于配体方法的一种替代方法，具有描述结合口袋整体相互作用能力的优势。在此，我们展示了针对拓扑异构酶I的SBPs的开发，拓扑异构酶I是一种抗癌靶点，其具有由蛋白质和DNA原子组成的独特配体结合口袋。研究了用于聚类和选择药效团特征的不同方法，包括层次聚类和能量计算。此外，对SBPs的性能进行了回顾性评估，并与基于配体和复合物的药效团的性能进行了比较。SBPs成为虚拟筛选中的一种有效方法以及聚焦配体方法的一种补充方法。该研究进一步揭示，药效团特征聚类和选择方法的选择对虚拟筛选命中列表有很大影响。SBPs在虚拟筛选中的前瞻性应用表明，它们可成功用于鉴定新型拓扑异构酶抑制剂。
