Cytochrome P-450 Polymorphism

描述（由申请方提供）：肝脏、微粒体、细胞色素P450单加氧酶在多种药物、毒素和内生菌的代谢和清除中发挥关键保护作用。本申请的长期目标是鉴定决定个体人P450酶的底物选择性的结构特征。活性位点特征影响底物选择性、抑制潜力、药物氧化的区域选择性以及药物-药物相互作用和活化动力学的发生。最近的结构比较P450的1A 2，2A 6，2C 8，2C 9和3A 4在复杂的基板或抑制剂表明独特的方面，每个活性位点，有助于基板的选择性，包括水合状态，化学特性和定位的活性位点残基，以及施加在这些结合决定因素的变化，通过改变活性位点的拓扑结构。这强调了确定与结构上不同的药物复合的单个酶的多种结构以了解构象灵活性对药物结合的贡献的必要性。P450 1A 2，2D 6，2C 19和2C 9 *3的活性位点结构的特定变化，通过与化学上不同的底物，抑制剂和激活剂，单独或组合的相互作用诱导，将被确定为描绘的适应性变化的范围，可以发生每种酶。P450 2A 6是人体内主要的尼古丁氧化酶。对与不同抑制剂复合的2A 6活性位点的分析表明了几个相对静态的特征，这些特征可以有效地用于基于结构的设计更有效和选择性的抑制剂，这些抑制剂将具有作为戒烟治疗助剂的潜在益处。将评估先导化合物与活性位点的互补性、结合强度以及相对于其他P450对2A 6的特异性。还将确定P450 1B 1、3A 5和3A 7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结构与功能相关知识的重大空白，并为预测药物代谢提供重要信息和工具。

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.