Cytochrome P-450 Polymorphism

细胞色素P450单加氧酶通常决定候选药物的清除，限制其治疗作用。 功效。这些酶也可能是脱靶毒性的来源。我们的长期目标是了解 P450酶底物识别的结构决定因素。无论是个人还是集体， 药物代谢P450可以代谢结构多样的底物，这可能反映在 部分酶的灵活性和底物结合的结构适应性。这突出表明 需要确定与结构不同的药物复合的单个酶的多种结构， 了解构象灵活性对药物结合的贡献。活性部位的具体变化 通过与化学多样性底物相互作用诱导的P450 1A 2、2C 19和3A 5的结构，或 将鉴定抑制剂以描绘每种酶可能发生的适应性变化的范围。 此外，还将分析P450 2 J2、3A 7和代表性家族4A酶的活性位点拓扑结构。 决心确定控制这些重要功能贡献的结构特征， 酶对药物代谢以及对外源性物质和过量内源性化合物的清除的影响。 总的来说，这些研究将解决我们对P450结构的认识中的重大空白，因为它涉及到 功能，并为药物开发中的先导化合物优化提供重要信息和工具， 提高疗效并降低代谢药物-药物相互作用风险。

Cytochrome P450 monooxygenases often determine the clearance of candidate drugs limiting their therapeutic efficacy. These enzymes can also be sources of 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 1A2, 2C19 and 3A5 induced by interaction with chemically diverse substrates or inhibitors will be identified to delineate the range of adaptive changes that can occur for each enzyme. Additionally, the active site topologies of P450s 2J2, 3A7 and representative family 4A enzymes will also be determined to identify structural characteristics that control the important functional contribution made by these enzymes to drug metabolism and to 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 lead compound optimization in drug development to improve efficacy and reduce risks of metabolic drug-drug interactions.