COMPUTATIONAL DOCKING STUDIES OF NITROANISOLES WITH CYP2E1

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 微体P450(P450或CYP对于特定的异构体)氧化一类结构不同的化合物，包括类固醇、脂肪酸、抗生素和各种外来的、具有生物活性的(异生)化学物质，如药物、食品添加剂和环境污染物。P450反应的体外动力学图谱为阐明P450活性的生物学作用提供了重要工具。该策略提供了描述P450催化反应的特异性和效率的有价值的参数。对P450代谢的重要性和后果的了解有助于药物设计、食品安全指南和有关污染物暴露的环境法规，因此对P450反应的准确建模至关重要。虽然双曲线动力学曲线是典型的，但越来越多的P450反应表现出非双曲线动力学曲线。这些结果不符合用于传统双曲线动力学剖面的Michaelis-Menten模型，而是需要更复杂的机理。尽管人们对这些P450的活性进行了大量的研究，但对观察到的细胞色素P450的非双曲线反应却知之甚少。 硝基苯甲醚是一类具有强烈毒性和致癌性的化合物，对人类构成相当大的危险。这些污染物广泛分布在工作场所，特别是染料行业，以及由于柴油和汽油发动机排放的废气、环境空气颗粒物和有毒物质泄漏造成的环境。已经做出了重大努力，确定了负责硝基苯甲醚解毒的产物和相应的P450；然而，描述这些化合物向非活性代谢物流动的动力学曲线需要研究。我们将通过两种不同的对接方法生成配体配合物的计算模型，以确定结合配体的化学计量比配合物和相应的接触残基。这些模型结合生物物理和生化数据，将使我们能够确定与致癌硝基苯甲醚解毒相关的CYP2E1的结构-功能关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Microsomal P450s (P450 or CYP for a particular isoform) oxidize a structurally diverse class of compounds including steroids, fatty acids, antibiotics, and a wide variety of foreign, biologically active (xenobiotic) chemicals, such as drugs, food additives, and environmental contaminants. In vitro kinetic profiling of P450 reactions provides an important tool for elucidating the biological role of P450 activity. The strategy provides valuable parameters that describe the specificity and efficiency of P450-catalyzed reactions. Knowledge of the significance and consequence of P450 metabolism facilitates drug design, food safety guidelines, and environmental regulations regarding exposure to pollutants, and thus accurate modeling of P450 reactions is critical. Though hyperbolic kinetic profiles are typical, a growing number of P450 reactions demonstrate non-hyperbolic kinetic profiles. These results do not conform to the Michaelis-Menten model used for traditional hyperbolic kinetic profiles, and instead require more complex mechanisms. Despite significant efforts to study the activity of those P450s, little is known about non-hyperbolic reactions observed for CYP2E1. Nitroanisoles are members of class of potent toxic and carcinogenic compounds, presenting a considerable danger to the human population. These pollutants are widely distributed in workplaces, especially dye industries, and the environment due to emissions from diesel and gasoline engines, ambient air particulate matter, and toxic spills. Significant efforts have identified products and the corresponding P450s responsible for nitroanisole detoxification; however, the kinetic profiles that describe the flux of these compounds to inactive metabolites require investigation. We will generate computational models of liganded complexes through two different docking approaches to identify the stoichiometry complexes and corresponding contact residues for bound ligands. These models, combined with biophysical and biochemical data, will allow us to determine the structure-function relationships for CYP2E1 relevant to the detoxification of carcinogenic nitroanisoles.