Cytochrome P-450 Polymorphism

描述（由申请人提供）：肝脏，微粒体，细胞色素P450单加氧酶在多种药物，毒素和内源性药物的代谢和清除中发挥重要的保护作用。该应用程序的长期目标是确定确定个体人类P450酶的底物选择性的结构特征。活性位点特性影响底物选择性、抑制电位、药物氧化的区域选择性以及药物-药物相互作用的发生和活化动力学。通过比较P450s 1A2、2A6、2C8、2C9和3A4在配合物中与底物或抑制剂的最新结构，可以发现每个活性位点的独特之处，包括水合状态、活性位点残基的化学特性和定位，以及活性位点拓扑结构的改变对这些结合决定因素的影响。这强调了确定结构不同药物复合物中单个酶的多种结构的必要性，以了解构象灵活性对药物结合的贡献。P450s 1A2、2D6、2C19和2C9*3的活性位点结构通过单独或联合与化学上不同的底物、抑制剂和活化剂相互作用引起的特异性变化将被确定，以描绘每种酶可能发生的适应性变化的范围。P450 2A6是人类体内主要的尼古丁氧化酶。对不同抑制剂复合物中2A6活性位点的分析表明，一些相对静态的特征可以有效地用于基于结构的更有效和选择性抑制剂的设计，这些抑制剂将具有作为戒烟治疗辅助的潜在益处。将评估先导化合物与活性位点的互补性、结合强度以及2A6相对于其他p450的特异性。还将确定P450s 1B1, 3A5和3A7的活性位点拓扑结构，以确定控制这些酶对药物代谢的重要功能贡献的结构特征。总的来说，这些研究将解决我们对P450结构与功能相关的知识的重大空白，并为预测药物代谢提供重要的信息和工具。

DESCRIPTION (provided by applicant): Hepatic, microsomal, cytochrome P450 monooxygenases provide a crucial protective role in the metabolism and clearance of a wide array of drugs, toxins and endobiotics. The long term objective of this application is to identify structural features that determine the substrate selectivity of individual human P450 enzymes. Active site characteristics affect substrate selectivity, inhibitory potential, the regioselectivity of drug oxidation, as well as the occurrence of drug-drug interactions and activation kinetics. Comparison of recent structures for P450s 1A2, 2A6, 2C8, 2C9 and 3A4 in complex with substrates or inhibitors indicate unique aspects of each active site that contribute to substrate selectivity including the hydration state, the chemical characteristics and positioning of active site residues, as well as the changes imposed on these binding determinants by alterations in active site topology. This underscores the necessity to determine multiple structures of individual enzymes in complex with structurally dissimilar drugs to understand the contribution of conformational flexibility to drug binding. Specific changes in the active site architectures of P450s 1A2, 2D6, 2C19 and 2C9*3 induced by interaction with chemically diverse substrates, inhibitors and activators, alone or in combination, will be identified to delineate the range of adaptive changes that can occur for each enzyme. P450 2A6 is the principal nicotine oxidase in humans. Analysis of the 2A6 active site in complex with different inhibitors indicates several relatively static features that can be productively exploited for the structure based design of more efficacious and selective inhibitors that would have potential benefits as therapeutic aids for smoking cessation. Lead compounds will be assessed for complementarity with the active site, strength of binding, and specificity for 2A6 relative to other P450s. The active site topologies of P450s 1B1, 3A5 and 3A7 will also be determined to identify structural characteristics that control the important functional contribution made by these enzymes to drug metabolism. Collectively, these studies will address significant gaps in our knowledge of P450 structure as it relates to function, and provide important information and tools for prediction of drug metabolism.