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，酒精滥用的患病率仅占总人口的4.6%（约960万），而直接酒精依赖的患病率仅占总人口的3.8%（约790万）。迄今为止，还没有发现一种药物治疗对所有酗酒者都有效。这一合作项目集合了计算药物设计、结构生物学和醛脱氢酶2酶学方面的专业知识，所有这些都将在该奖项的2年时间框架内集中在一个目标上——发现和开发一种具有合适药代动力学特性的高效选择性药物，用于抑制酒精依赖的醛脱氢酶2。我们的长期目标是利用具有合适体内疗效和药代动力学特征的小有机分子靶向ALDH2，并可作为目前批准的酒精依赖药物治疗方法的辅助手段。纳曲酮或阿坎普罗酸)，以改善临床结果。并非所有的酗酒者对某种治疗都有积极的反应，这一事实说明了开发治疗酒精使用障碍的药物治疗药物库的重要性，也说明了发现有能力减少饮酒的新化合物的重要性。我们的假设是，联合治疗方案与一种药物以与纳曲酮或阿坎前列酯正交的方式发挥其作用将改善治疗结果。在我们的第一个目标中，我们执行计算搜索以确定额外的ALDH2抑制剂。我们介绍了对计算方法的几个改进，包括筛选显著较大的文库和靶向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，进行了一系列体外分析，以评估aim 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功效研究。印第安纳大学通过一系列核心设施来促进这一过程，处于独特的地位。

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.