Three‐Dimensional Quantitative Structure Activity Relationship for Cyp2d6 Substrates

R. Snyder, R. Sangar, Jibo Wang, S. Ekins
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引用次数: 49

Abstract

Without a crystallized structure for a human cytochrome P450, the use of computational molecular modeling is one approach to examine the active site requirements of substrate and inhibitor specificity. CYP2D6 is undoubtedly the most studied polymorphic human CYP and it is therefore desirable for drug companies to limit its role in the metabolism of drug-candidate molecules due to the need for therapeutic drug monitoring. The purpose of this study was to use a three-dimensional quantitative structure activity relationship (3D-QSAR) approach for understanding the CYP2D6 substrate requirements. Using literature Km values (n=24) derived solely from recombinant sources we were able to build and test one such pharmacophore. This was able to significantly rank-order using the (Spearman's rho coefficient 0.55, p=0.0022) predicted against observed literature Km values (n=28) also derived from recombinant sources. The pharmacophore generated in this study was then fitted into the homology model of the human CYP2D6 based on an alignment of bacterial CYPs and the mammalian CYP2C5 to further validate these modeling approaches. Such models as these represent important tools for quantitative prediction of the level of interaction between a molecule and CYP2D6.
Cyp2d6底物的三维定量构效关系
没有人类细胞色素P450的结晶结构,使用计算分子模型是检查底物和抑制剂特异性的活性位点要求的一种方法。CYP2D6无疑是研究最多的多态性人类CYP,因此,由于治疗药物监测的需要,制药公司希望限制其在候选药物分子代谢中的作用。本研究的目的是使用三维定量结构活性关系(3D-QSAR)方法来了解CYP2D6底物需求。利用仅来源于重组来源的文献Km值(n=24),我们能够构建并测试一个这样的药效团。使用(Spearman's rho系数0.55,p=0.0022)预测也来自重组来源的观察文献Km值(n=28),这能够显著地排序。然后,基于细菌CYP2D6和哺乳动物CYP2C5的比对,将本研究生成的药效团拟合到人类CYP2D6的同源性模型中,进一步验证这些建模方法。这些模型是定量预测分子与CYP2D6相互作用水平的重要工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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