Cytochrome P-450 Polymorphism

描述(由申请人提供)：细胞色素P450单加氧酶通常决定限制其疗效的候选药物的清除。这些酶也可能是非靶标毒性的来源。我们的长期目标是了解P450酶识别底物的结构决定因素。集体和单独地，人类药物代谢P450可以代谢不同范围的底物，这可能在一定程度上反映了每个酶的灵活性和对底物结合的结构适应。这强调了有必要确定结构不同的药物复合体中单个酶的多种结构，以了解构象灵活性对药物结合的贡献。将确定P450的1B1、1A2、2D6和2C19的活性部位结构的特定变化，这些变化是由单独或联合使用化学上不同的底物、抑制剂和激活剂引起的，以描述每种酶可能发生的适应性变化的范围。此外，还将确定P450s 2J2、3A5和3A7的活性部位拓扑以及具有代表性的家族4酶，以确定控制这些酶对药物代谢和清除外源物质和过量内源化合物的重要功能贡献的结构特征。总而言之，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。 公共卫生相关性：这些研究将提供新的信息来指导药物设计，以避免因细胞色素P450介导的药物代谢而导致的疗效限制和不良的靶外效应。这将使作为药物开发目标的广泛治疗领域受益。

DESCRIPTION (provided by applicant): Cytochrome P450 monooxygenases often determine the clearance of candidate drugs limiting their efficacy. These enzymes can also be sources for off-target toxicity. Our long term objective is to understand the structural determinants of substrate recognition by P450 enzymes. Collectively and individually the human drug metabolizing P450s can metabolize structurally diverse range of substrates, and this is likely to reflect in part the flexibility of each enzyme and structural adaptations for substrate binding. 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 1B1, 1A2, 2D6, and 2C19 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. Additionally, the active site topologies of P450s 2J2, 3A5 and 3A7 as well as representative family 4 enzymes will also be determined to identify structural characteristics that control the important functional contribution made by these enzymes to drug metabolism and the clearance of xenobiotics and excess endogenous compounds. 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 the prediction of drug metabolism. PUBLIC HEALTH RELEVANCE: These studies will provide new information to guide drug design in order to avoid limitations of efficacy and undesirable off-target effects resulting from cytochrome P450 mediated drug metabolism. This will benefit a wide range of therapeutic areas targeted for drug development.