COMPUTATIONAL DOCKING STUDIES OF NITROANISOLES WITH CYP2E1

硝基苯甲醚与 CYP2E1 的计算对接研究

• 批准号: 7959442
• 负责人: MARTIN PERRY
• 金额: $ 1.59万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959442
• 关键词: Air; Antibiotics; Arkansas; Biochemical; Biological; Biomedical Research; CYP2E1 gene; Chemicals; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Cytochrome P450; Data; Docking; Drug Design; Drug Metabolic Detoxication; Dyes; Environment; Environmental Pollution; Exposure to; Fatty Acids; Food Additives; Food Safety; Funding; Gasoline; Grant; Guidelines; Human; In Vitro; Industry; Institution; Investigation; Kinetics; Knowledge; Ligand Binding; Ligands; Metabolism; Modeling; Particulate Matter; Pharmaceutical Preparations; Population; Protein Isoforms; Reaction; Regulation; Research; Research Personnel; Resources; Role; Source; Specificity; Steroids; Structure-Activity Relationship; United States National Institutes of Health; Workplace; Xenobiotics; member; pollutant; stoichiometry; tool

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 微粒体P450（P450或P450的一种特殊亚型）氧化结构多样的化合物，包括类固醇，脂肪酸，抗生素和各种各样的外来生物活性（异生素）化学品，如药物，食品添加剂和环境污染物。P450反应的体外动力学分析为阐明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。了解P450代谢的重要性和后果有助于药物设计、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曲线的Michaelis-Menten模型，而是需要更复杂的机制。尽管对这些P450的活性进行了大量研究，但对CYP 2 E1观察到的非双曲线反应知之甚少。 硝基苯甲醚是一种有毒、致癌的化合物，对人类有很大的危害。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的排放，环境空气颗粒物和有毒物质泄漏而产生的环境中。重大的努力已经确定的产品和相应的P450负责硝基苯甲醚解毒，但是，动力学曲线，描述这些化合物的流量，以非活性代谢物需要调查。我们将通过两种不同的对接方法生成配体复合物的计算模型，以确定化学计量复合物和相应的结合配体的接触残基。这些模型，结合生物物理和生物化学数据，将使我们能够确定CYP 2 E1的结构-功能关系的致癌性硝基苯甲醚的解毒。