Targeting ALDH2 for Adjuvant Treatment of Alcohol Dependence

靶向 ALDH2 辅助治疗酒精依赖

基本信息

批准号：
7977119
负责人：
THOMAS D. HURLEY
金额：
$ 23.1万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7977119
关键词：
Acetaldehyde Adjuvant Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Aldehydes Alleles Animals Applications Grants Asians Award Binding Biochemical Biological Assay CYP2C9 gene Caco-2 Cells Carboxylic Acids Clinical Clinical Pharmacology Combined Modality Therapy Complement Complex Computer Simulation Core Facility Cyanamide Cytochrome P450 Cytochromes DNA Binding Data Development Disulfiram Docking Drug Design Drug Industry Drug Kinetics Environment Enzymatic Biochemistry Enzymes Ethanol Metabolism Evaluation Exhibits Follow-Up Studies Funding Future General Population Generations Goals Grant Hand Head Human In Vitro Indiana Individual Institutes Ion Channel Lead Legal patent Libraries Measures Metabolic Mitochondria Molecular Molecular Conformation Naltrexone Outcome Permeability Pharmaceutical Preparations Population Positioning Attribute Prevalence Process Property Publishing Qualifying Research Risk Role Sampling Screening procedure Series Serum Albumin Site Solutions Specificity Staging Structure System Taxes Therapeutic Time Treatment Protocols Treatment outcome Universities Work X ray diffraction analysis X-Ray Diffraction acamprosate alcohol research alcohol use disorder alcoholism therapy aldehyde dehydrogenases base chemical synthesis cheminformatics combinatorial enzyme structure expectation experience follow-up improved in vitro Assay in vivo inhibitor/antagonist medical schools molecular dynamics multidisciplinary novel oxidation problem drinker public health relevance small molecule small molecule libraries structural biology

项目摘要

DESCRIPTION (provided by applicant): The National Institute of Alcohol Abuse and Alcoholism estimates the prevalence of alcohol abuse at just over 4.6% of the general population (~9.6 million) and of frank alcohol dependency at just over 3.8% of the population (~7.9 million). To date, no single pharmacotherapeutic agent has been found to be effective for all alcoholics. This collaborative venture brings together expertise in computational drug design, structural biology and enzymology of aldehyde dehydrogenase 2, all of which will be focused during the 2 year timeframe of this award on a single goal - discover and develop a highly potent and selective agent with suitable pharmacokinetic properties for the inhibition of aldehyde dehydrogenase 2 for alcohol dependency. Our long term objective is to target ALDH2 with small organic molecules that possess suitable in vivo efficacy and pharmacokinetic profile and could serve as a adjuvant to currently approved pharmacological approaches toward alcohol dependence therapies (eg. naltrexone or acamprosate) in order to improve the clinical outcomes. The fact that not all alcoholics respond positively to a given treatment exemplifies the importance of developing an arsenal of pharmacotherapeutic agents for the treatment of alcohol use disorders and illustrates the importance of identifying new compounds that have the ability to decrease alcohol drinking. It is our hypothesis that a combined treatment regimen with a drug that exerts its effects in a manner orthogonal to either naltrexone or acamprosate will improve treatment outcomes. In our first aim we perform a computational search to identify additional ALDH2 inhibitors. We introduce several improvements to the computational approach including screening significantly larger libraries and targeting alternative sites and conformational states of the enzyme. In the second aim we characterize the activity of these compounds through enzymology and biophysical studies. In our third aim, a series of in vitro assays are performed to assess the pharmacokinetic properties of the most promising compounds that emerge from Aim 2. This work will set the stage for a follow-up study that will consist of a computational combinatorial search in a multidisciplinary effort that will involve chemical synthesis, biochemical and structural evaluation, and animal pharmacokinetic and efficacy studies. The Indiana University is uniquely positioned through a series of Core facilities to facilitate this process. PUBLIC HEALTH RELEVANCE: Mitochondrial aldehyde dehydrogenase (ALDH2) is most commonly associated with its role in alcohol metabolism and catalyzes the NAD+-dependent oxidation of a broad spectrum of endogenous and biogenic aldehydes to their corresponding carboxylic acids. Inhibition of ALDH2 with small molecules that possess suitable pharmacokinetic properties and efficacy could lead to pharmacotherapeutics to assist in the treatment of alcohol dependence.

描述（由申请人提供）：国家酒精滥用和酒精中毒研究所估计，总人口中酒精滥用率略高于 4.6%（约 960 万人），而直接酒精依赖率略高于总人口的 3.8%（约 3.8%）。 790 万）。迄今为止，尚未发现单一药物治疗剂对所有酗酒者有效。该合作项目汇集了乙醛脱氢酶 2 的计算药物设计、结构生物学和酶学方面的专业知识，所有这些都将在该奖项的 2 年期限内集中于一个目标 - 发现和开发一种高效且具有选择性的药物，并具有合适的性能。抑制酒精依赖性乙醛脱氢酶 2 的药代动力学特性。我们的长期目标是用小有机分子靶向 ALDH2，这些小分子具有合适的体内功效和药代动力学特征，并且可以作为目前批准的酒精依赖治疗药理学方法（例如纳曲酮或阿坎酸）的佐剂，以改善临床结果。并非所有酗酒者都对特定治疗产生积极反应，这一事实说明了开发治疗酒精使用障碍的药物治疗剂库的重要性，并说明了识别能够减少饮酒的新化合物的重要性。我们的假设是，采用与纳曲酮或阿坎酸正交的方式发挥作用的药物的联合治疗方案将改善治疗结果。在我们的第一个目标中，我们进行计算搜索来识别其他 ALDH2 抑制剂。我们对计算方法进行了一些改进，包括筛选更大的文库以及针对酶的替代位点和构象状态。在第二个目标中，我们通过酶学和生物物理学研究来表征这些化合物的活性。在我们的第三个目标中，进行了一系列体外测定，以评估目标 2 中出现的最有希望的化合物的药代动力学特性。这项工作将为后续研究奠定基础，该研究将包括计算组合搜索这是一项多学科的努力，涉及化学合成、生化和结构评估以及动物药代动力学和功效研究。印第安纳大学拥有独特的地位，通过一系列核心设施来促进这一过程。公共健康相关性：线粒体醛脱氢酶 (ALDH2) 最常与其在酒精代谢中的作用相关，并催化 NAD+ 依赖性广谱内源性和生物醛氧化为其相应的羧酸。用具有合适的药代动力学特性和功效的小分子抑制 ALDH2 可能会导致药物治疗有助于治疗酒精依赖。