Cytochrome P450 Models for Risk Assessment

描述（由申请人提供）：该补助金的继续将支持预测细胞色素P450介导的区域选择性和速率的计算工具的持续开发。细胞色素P450酶家族负责大量化学物质的代谢。该酶家族还负责将许多化学品生物活化为导致毒性和致癌性的活性中间体。因此，这种酶家族的计算模型将在科学和公共卫生的许多领域发挥重要作用。该提案的总体目标是建立可用作风险评估组成部分的计算模型。这些方法将同样适用于工业过程中更安全的化学品的设计，作为药物设计的工具，并作为虚拟化学品库的毒性评估工具。具体而言，该资助将1）扩展现有的计算模型，以包括更多的P450介导的反应，2）进行实验，将允许预测P450介导的反应的速率，和3）建立CYP 2 E1的三维结合亲和力模型，CYP 2 E1是参与毒素和致癌物生物活化的最重要的P450酶之一。实验设计结合了有机合成，分子生物学，蛋白质生物化学，分析质谱，放射化学方法学和计算化学的使用。因此，这一建议还有助于培训科学家在化学/生物学界面上使用多学科方法来理解特定的科学问题。

DESCRIPTION (provided by applicant): The continuation of this grant will support the continued development of computational tools for predicting cytochrome P450 mediated regioselectivities and rates. The cytochrome P450 enzyme family is responsible for metabolism of a large number of chemicals. This enzyme family is also responsible for the bioactivation of many chemicals to reactive intermediates responsible for toxicity and carcinogenicity. Therefore, computational models for this enzyme family will play an important role in many areas of science and public health. The overall goal of this proposal is to establish computational models that can be used as a component in risk assessment. These methods will be equally applicable to the design of safer chemicals for industrial processes, as tools for drug design, and as tools for the toxicity assessment of virtual libraries of chemicals. Specifically, this grant will 1) extend existing computational models to include more P450 mediated reactions, 2) perform experiments that will allow for the prediction of the rates of P450 mediated reactions, and 3) establish 3-dimensional binding affinity models for CYP2E1, one of the most important P450 enzymes involved in the bioactivation of toxins and carcinogens. The experimental design combines the use of organic synthesis, molecular biology, protein biochemistry, analytical mass spectrometry, radiochemical methodology, and computational chemistry. Thus, this proposal also helps to train scientists in the use of multidisciplinary approaches, at the chemical/biological interface, to understanding a given scientific problem.