Virtual High Throughput Screening: Specific Mechanism-based Inhibitors of CYP2E1

虚拟高通量筛选：基于特定机制的 CYP2E1 抑制剂

基本信息

批准号：
8029735
负责人：
Haoming Zhang
金额：
$ 7.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8029735
关键词：
Abbreviations Acetaminophen Active Sites Affinity Alcohol dehydrogenase Alcohol-Related Disorders Alcoholic Liver Diseases Alcoholism Alcohols Animal Model Basic Science Binding Biochemical Biological Assay Biological Factors Brain CYP1A2 gene CYP2B4 gene Carbon Tetrachloride Cell Line Chemicals Clinic Clinical Trials Collection Computer software Cytochrome P-450 CYP2E1 Cytochrome P450 Cytochromes b5 Development Disease Docking Effectiveness Ethanol Ethanol toxicity Fetal Alcohol Syndrome Free Energy Genomics Goals Health Hepatotoxicity Human Impairment Inhibitory Concentration 50 Lead Libraries Ligands Lipid Peroxidation Liver Liver diseases Malignant Neoplasms Mediating Methods Michigan Mixed Function Oxygenases Molecular Weight NADPH-Ferrihemoprotein Reductase Nitrosamines Outcome Oxidative Stress Pathogenesis Pharmaceutical Preparations Play Preclinical Drug Evaluation Prevention Process Public Health Reactive Oxygen Species Recording of previous events Risk Role Screening procedure Selection Criteria Specificity Testing Therapeutic Agents Time Tissues Toxic effect United States Food and Drug Administration Universities Up-Regulation alcohol abuse therapy aldehyde dehydrogenases base cancer risk chronic alcohol ingestion cost effective heme a hepatotoxin high throughput screening in vivo inhibitor/antagonist innovation macromolecule oxidation prevent problem drinker receptor small molecule virtual

项目摘要

DESCRIPTION (provided by applicant): Cytochrome P450 2E1 (CYP2E1) is a heme-containing monooxygenase that catalyzes the oxidation of a number of hepatotoxins and procarcinogens including ethanol, acetaminophen, nitrosamines, and carbon tetrachloride, among many others. CYP2E1 is highly inducible in human livers by alcohol. Upregulation of CYP2E1 by alcohol enhances hepatotoxicity and increases the risk of developing cancer in alcoholics. It is thought that CYP2E1 plays an important role in the pathogenesis of alcohol-induced liver injury due to CYP2E1-mediated oxidative stress and lipid peroxidation. Inhibition of CYP2E1 activity has been shown to minimize the toxicity of alcohol. However, existing CYP2E1 inhibitors cannot be used in vivo because of their promiscuity and toxicity. There is a need to develop specific and non-toxic CYP2E1 inhibitors that can be used both for basic research to investigate the specific role of CYP2E1 in alcohol-related diseases and for use in the clinic to treat and prevent alcoholism. I hypothesize that potent and specific mechanism-based inhibitors of CYP2E1 can be identified from small ligand libraries through virtual high throughput screening (vHTS). In this proposal, I plan to test this hypothesis with two specific aims: 1) to screen approximately 55,000 acetylenic compounds in small ligand libraries using dual selection criteria and 2) to analyze the potency and specificity of the vHTS hits by biochemical assays. The outcome of this proposal will yield approximately a dozen lead inhibitors for CYP2E1 that can be used to accelerate the development of therapeutic agents. PUBLIC HEALTH RELEVANCE: Chronic alcohol consumption leads to a host of health issues including brain impairment, fetal alcohol syndrome, increased risk of cancer, and alcohol liver diseases. Therefore, the prevention and treatment of alcohol-related diseases are critically important to public health. In this project, I propose to identify new, specific inhibitors for CYP2E1. The long-term goal is to develop CYP2E1-specific inhibitors that can be used clinically to treat and prevent alcohol liver diseases. This approach may also be applied to identify specific inhibitors for other cytochrome P450 targets.

描述（申请人提供）：细胞色素 P450 2E1 (CYP2E1) 是一种含血红素的单加氧酶，可催化多种肝毒素和致癌物的氧化，包括乙醇、对乙酰氨基酚、亚硝胺和四氯化碳等。 CYP2E1 在人类肝脏中很容易被酒精诱导。酒精上调 CYP2E1 会增强肝毒性，并增加酗酒者患癌症的风险。人们认为CYP2E1在酒精性肝损伤的发病机制中起重要作用，这是由于CYP2E1介导的氧化应激和脂质过氧化所致。抑制 CYP2E1 活性已被证明可以最大限度地减少酒精的毒性。然而，现有的CYP2E1抑制剂由于其混杂性和毒性而不能在体内使用。需要开发特异性且无毒的CYP2E1抑制剂，既可用于基础研究以研究CYP2E1在酒精相关疾病中的具体作用，又可用于临床治疗和预防酒精中毒。我假设可以通过虚拟高通量筛选 (vHTS) 从小型配体库中鉴定出有效且特定的基于机制的 CYP2E1 抑制剂。在本提案中，我计划通过两个具体目标来检验这一假设：1）使用双重选择标准在小型配体库中筛选大约 55,000 种炔属化合物，2）通过生化测定分析 vHTS 命中的效力和特异性。该提案的结果将产生大约十几种 CYP2E1 的先导抑制剂，可用于加速治疗药物的开发。公共健康相关性：长期饮酒会导致一系列健康问题，包括大脑损伤、胎儿酒精综合症、癌症风险增加和酒精肝疾病。因此，预防和治疗与酒精相关的疾病对公众健康至关重要。在这个项目中，我建议寻找新的、特异性的 CYP2E1 抑制剂。长期目标是开发CYP2E1特异性抑制剂，可用于临床治疗和预防酒精肝疾病。该方法还可用于鉴定其他细胞色素 P450 靶标的特异性抑制剂。