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（由申请人提供）：细胞色素P450 2E1（CYP2E1）是一种含血红素的单加掺杂酶，可催化许多乙醇，乙酰氨基酚，硝酸胺和碳四氯糖胺等许多乙醇毒素和procarcinogens的氧化。 CYP2E1通过酒精在人肝中高度诱导。酒精对CYP2E1的上调可增强肝毒性，并增加酗酒者患癌症的风险。人们认为，CYP2E1在由于CYP2E1介导的氧化应激和脂质过氧化引起的酒精诱导的肝损伤的发病机理中起重要作用。 CYP2E1活性的抑制已显示可最大程度地减少酒精的毒性。但是，由于其滥交和毒性，现有的CYP2E1抑制剂不能在体内使用。有必要开发特异性和无毒的CYP2E1抑制剂，这些抑制剂既可以用于基础研究，以研究CYP2E1在酒精相关疾病中的特定作用，并在诊所使用以治疗和预防酒精中毒。我假设可以通过虚拟高吞吐量筛选（VHTS）从小配体库中鉴定出有效的基于机制的CYP2E1的抑制剂。在此提案中，我计划以两个具体的目的检验该假设：1）使用双重选择标准和2）分析VHTS通过生物化学分析命中的效力和特异性。该提案的结果将对CYP2E1产生大约十二个铅抑制剂，可用于加速治疗剂的发育。公共卫生相关性：长期饮酒会导致许多健康问题，包括大脑障碍，胎儿酒精综合症，增加的癌症风险和酒精肝疾病。因此，与酒精相关疾病的预防和治疗对公共卫生至关重要。在这个项目中，我建议确定CYP2E1的新的特定抑制剂。长期目标是开发CYP2E1特异性抑制剂，这些抑制剂可在临床上用于治疗和预防酒精肝疾病。该方法还可以应用于确定其他细胞色素P450靶标的特定抑制剂。