Cytochrome P-450 Polymorphism

细胞色素P450单加氧酶通常决定限制其治疗的候选药物的清除 功效。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。集体和个人的人类 药物代谢P450可以代谢各种结构不同的底物，这可能反映在 每种酶的灵活性和底物结合的结构适应性。这突显了 确定结构不同药物复合体中单个酶的多重结构的必要性 了解构象灵活性对药物结合的贡献。活动站点中的特定更改 P450的1A2、2C19和3A5与不同的底物相互作用诱导的构型 将确定抑制剂，以描述每种酶可能发生的适应性变化的范围。 此外，P450的2J2、3A7和代表家族4A酶的活性位点拓扑也将是 决心确定结构特征，这些结构特征控制着 酶对药物新陈代谢和清除外源物质和过量内源性化合物的作用。 总的来说，这些研究将解决我们对P450结构的认识上的重大空白，因为它与 功能，为药物开发中的先导化合物优化提供重要的信息和工具 提高疗效，降低代谢性药物相互作用的风险。

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.