Quantitative binding models for CYP2C9 based on benzbromarone analogues
Quantitative binding models for CYP2C9 based on benzbromarone analogues
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DOI：
10.1021/bi049651o
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发表时间：
2004-06-08
期刊：
影响因子：
2.9
通讯作者：
Jones, JP
中科院分区：
文献类型：
--
作者：
Locuson, CW;Rock, DA;Jones, JP
参与异源代谢的细胞色素P450(CYP)亚型是一种酶，由于其广泛的特异性和动态的蛋白质-底物相互作用，其底物选择性仍然难以预测。为了揭示细胞色素CYP2C9的特异性决定因素，一个新的苯溴马龙(Bzbr)抑制剂文库被用来重新评估它的药效团。CoMSIA与bzbr配体一起使用，以生成定量结合模型和三维等高线图，以精确定位预测的相互作用，这些相互作用对与2C9的结合至关重要。由于这类化合物比任何其他化合物对2C9更有效，软件认为最理想的小分子特性被用来使用新的突变和结构数据来解决蛋白质-配体相互作用。9个新的BZBR类似物提供了证据，表明特定的静电和疏水相互作用对2C9的S特异性贡献最大。其中三个新类似物是bzbr的较好的同位素体，它们在苯酚附近含有较大的基团，并具有更高的pK(A)值。这些配体验证了阴离子底物与2C9结合具有更高亲和力的假设。由于它们比以前的非酸性类似物具有更高的亲和力，因此酚环上大体积基团的重要性似乎被低估了。CoMSIA模型预测，这些体积较大的基团有利于它们的疏水性，而在酮氧而不是苯酚氧上，负电荷更有利。这种酮与其他2C9底物的电负性基团的重叠表明它们是关键的正电荷受体。
The cytochrome P450 (CYP) isoforms involved in xenobiotic metabolism are enzymes whose substrate selectivity remains difficult to predict due to wide specificity and dynamic protein-substrate interactions. To uncover the determinants of specificity for cytochrome CYP2C9, a novel library of benzbromarone (bzbr) inhibitors was used to reevaluate its pharmacophore. CoMSIA was used with the bzbr ligands to generate both quantitative binding models and three-dimensional contour plots that pinpoint predicted interactions that are important for binding to 2C9. Since this class of compounds is more potent than any other toward 2C9, the small molecule properties deemed most ideal by the software were used to address protein-ligand interactions using new mutagenesis and structural data. Nine new bzbr analogues provide evidence that specific electrostatic and hydrophobic interactions contribute the most to 2C9's specificity. Three of the new analogues are better isosteres of bzbr that contain bulky groups adjacent to the phenol and have increased pK(a) values. These ligands test the hypothesis that anionic substrates bind with higher affinity to 2C9. Since they have higher affinity than the previous nonacidic analogues, the importance of bulky groups on the phenol ring appears to have been underestimated. CoMSIA models predict that these bulky groups are favorable for their hydrophobicity, while a negative charge is favored at the ketone oxygen rather than the phenol oxygen. The overlap of this ketone with electronegative groups of other 2C9 substrates suggests they act as key positive charge acceptors.