底物与 P-糖蛋白结合的结构贡献。一种 TOPS-MODE 方法。

Structural contributions of substrates to their binding to P-Glycoprotein. A TOPS-MODE approach.

机构信息

Department of Mathematics and Statistics, Institute of Complexity Systems, University of Strathclyde Glasgow, UK.

出版信息

Curr Pharm Des. 2010;16(24):2676-709. doi: 10.2174/138161210792389243.

PMID:20642431

Abstract

A topological substructural molecular design approach (TOPS-MODE) has been used to formulate structural rules for binding of substrates of P-glycoprotein (P-gp). We first review some of the models developed in the recent literature for predicting binding to P-gp. Then, we develop a model using TOPS-MODE, which is able to identify 88.4% of substrates and 84.2% of non-substrates. When the model is presented to an external prediction set of 100 substrates and 77 nonsubstrates it identifies correctly 81.8% of all cases. Using TOPS-MODE strategy we found structural contributions for binding to P-gp, which identifies 24 structural fragments responsible for such binding. We then carried out a chemico-biological analysis of some of the structural fragments found as contributing to P-gp binding of substrates. We show that in general the model developed so far can be used as a virtual screening method for identifying substrates of P-gp from large libraries of compounds.

摘要

拓扑子结构分子设计方法（TOPS-MODE）已被用于制定 P 糖蛋白（P-gp）底物结合的结构规则。我们首先回顾了近期文献中开发的一些用于预测与 P-gp 结合的模型。然后，我们使用 TOPS-MODE 开发了一个模型，该模型能够识别 88.4%的底物和 84.2%的非底物。当将该模型呈现给 100 个底物和 77 个非底物的外部预测集时，它正确识别了所有情况下的 81.8%。使用 TOPS-MODE 策略，我们发现了与 P-gp 结合的结构贡献，确定了 24 个负责这种结合的结构片段。然后，我们对一些被发现有助于底物与 P-gp 结合的结构片段进行了化学生物学分析。我们表明，总的来说，迄今为止开发的模型可以用作从化合物的大型文库中识别 P-gp 底物的虚拟筛选方法。