Cytochrome P450 2C9 Type II Binding Studies on Quinoline-4-Carboxamide Analogues
Cytochrome P450 2C9 Type II Binding Studies on Quinoline-4-Carboxamide Analogues
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DOI：
10.1021/jm8011257
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发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Jones, Jeffrey P.
中科院分区：
文献类型：
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作者：
Peng, Chi-Chi;Cape, Jonathan L.;Jones, Jeffrey P.
CYP 2C 9是负责药物代谢的重要P450蛋白。随着杂环化合物在药物设计中的使用增加，这些潜在的II型结合化合物的快速有效的药物前筛选对于避免药物不良反应是必不可少的。为了了解结合模式，我们使用喹啉-4-甲酰胺类似物来研究决定结构-活性关系的因素。这项研究的结果表明，更容易吡啶与氮帕拉的连接可以直接与铁血红素铁协调，但这是没有看到的Meta或邻位异构体。萘部分和Arg 108残基的π-阳离子相互作用也可有助于稳定活性位点空腔内的底物结合。II型底物结合亲和力由空间、静电和疏水性因素的组合决定;同时，它由孤对电子与血红素铁的配位强度增强。
CYP2C9 is a significant P450 protein responsible for drug metabolism. With the increased use of heterocyclic compounds in drug design, a rapid and efficient predrug screening of these potential type II binding compounds is essential to avoid adverse drug reactions. To understand binding modes, we use quinoline-4-carboxamide analogues to study the factors that determine the structure-activity relationships. The results of this study suggest that the more accessible pyridine with the nitrogen para to the linkage can coordinate directly with the ferric heme iron, but this is not seen for the meta or ortho isomers. The pi-cation interaction of the naphthalene moiety and Arg 108 residue may also assist in stabilizing Substrate binding within the active-site cavity. The type II substrate binding affinity is determined by the combination of steric, electrostatic, and hydrophobicity factors; meanwhile, it is enhanced by the strength of lone pair electrons coordination with the heme iron.