Targeting ALDH2 for Adjuvant 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，酗酒的流行率略高于总人口的4.6%(约960万人)，赤裸裸的酒精依赖仅占总人口的3.8%多一点(约790万人)。到目前为止，还没有发现一种药物治疗剂对所有酗酒者有效。这一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，在该奖项的两年时间框架内，所有这些专业知识都将集中在一个单一目标上--发现和开发一种具有适当药代动力学特性的高度有效和选择性的药物，用于抑制酒精依赖的乙醛脱氢酶2。我们的长期目标是以ALDH2为靶点，使其具有合适的体内疗效和药代动力学特征，并可作为目前批准的酒精依赖治疗的药理学方法的佐剂(例如。纳曲酮或氨基己酸酯)，以改善临床结果。并非所有酗酒者对某种治疗都有积极反应，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，并说明了确定有能力减少饮酒的新化合物的重要性。我们的假设是，与纳曲酮或氨基己酸酯以垂直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，我们进行计算搜索以确定其他ALDH2抑制剂。我们介绍了对计算方法的几个改进，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研究来表征这些化合物的活性。在我们的第三个目标中，我们进行了一系列体外测试，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，该研究将包括多学科努力中的计算组合搜索，包括化学合成、生化和结构评估，以及动物药代动力学和疗效研究。印第安纳大学通过一系列核心设施来促进这一过程，从而具有独特的地位。 与公共健康相关：线粒体乙醛脱氢酶(ALDH2)通常与其在酒精代谢中的作用有关，并催化广泛的内源和生物醛依赖NAD+氧化成相应的羧酸。用具有合适的药代动力学特性和疗效的小分子抑制ALDH2可能导致药物疗法来辅助酒精依赖的治疗。

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.