Quantitative structure-activity relationships within a homologous series of 7-alkoxyresorufins exhibiting activity towards CYP1A and CYP2B enzymes: molecular modelling studies on key members of the resorufin series with CYP2C5-derived models of human CYP1A1, CYP1A2, CYP2B6 and CYP3A4
Quantitative structure-activity relationships within a homologous series of 7-alkoxyresorufins exhibiting activity towards CYP1A and CYP2B enzymes: molecular modelling studies on key members of the resorufin series with CYP2C5-derived models of human CYP1A1, CYP1A2, CYP2B6 and CYP3A4
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DOI：
10.1080/00498250410001691316
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发表时间：
2004-06-01
期刊：
影响因子：
1.8
通讯作者：
Dickins, M
中科院分区：
文献类型：
--
作者：
Lewis, DFV;Lake, BG;Dickins, M
1.报道了7- n -烷氧基试卤灵同系物的定量构效关系（QSAR）结果。它们与参与其代谢的相关P450的同源性建模一致。利用与化合物平面性和其他形状参数相关的结构描述符，以及n -烷氧基试卤灵电子结构的某些特征，特别是电子密度和超离域性，生成涉及CYP 1A和CYP 2B酶的活性的QSAR.化合物亲脂性和与CYP 2B酶结合之间的二次关系是明显的，这表明7-戊氧基试卤灵的最大相互作用。这些迹象有助于从适合相关活性位点区域的最佳烷基链长度方面解释酶的选择性。4.根据7-烷氧基试卤灵，计算甲氧基、乙氧基、戊氧基和苄氧基试卤灵对CYP 1A 2或CYP 2B 6酶的结合亲和力，与K-m测定获得的实验值一致。
1. The results of quantitative structure-activity relationships (QSARs) within a homologous series of 7- n -alkoxyresorufins are reported. They are consistent with homology modelling of the relevant P450s involved in their metabolism.2. QSARs were generated for activities involving CYP1A and CYP2B enzymes with structural descriptors relating to compound planarity and other shape parameters, together with certain features of the n -alkoxyresorufin electronic structure, especially electron densities and superdelocalizabilities.3. A quadratic relationship between compound lipophilicity and binding to CYP2B enzymes was apparent, and which indicated maximal interaction for 7-pentoxyresorufin. Such indications help to explain enzyme selectivity in terms of optimal alkyl chain length for fitting within the relevant active site region.4. Calculation of the binding affinities for methoxy-, ethoxy-, pentoxy- and benzyloxy-resorufins towards either CYP1A2 or CYP2B6 enzymes, depending on the 7-alkoxyresorufin agree favourably with experimental values obtained from K-m determinations.