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，酒精滥用的流行率略高于一般人口的4.6%（约960万），而坦率的酒精依赖率略高于人口的3.8%（约790万）。到目前为止，还没有发现一种单一的药物对所有的酗酒者都有效。该合作企业汇集了计算药物设计，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年时间内集中在一个目标上-发现和开发具有合适药代动力学特性的高效选择性药物，用于抑制醛脱氢酶2的酒精依赖。我们的长期目标是用具有合适的体内功效和药代动力学特征的小有机分子靶向ALDH 2，并且可以作为目前批准的用于酒精依赖治疗的药理学方法的佐剂（例如，纳洛酮或阿坎酸）以改善临床结果。事实上，并非所有的酗酒者都对特定的治疗有积极的反应，这证明了开发一种治疗酒精使用障碍的药物库的重要性，并说明了鉴定能够减少饮酒的新化合物的重要性。我们的假设是，与以与纳洛酮或阿坎酸正交的方式发挥其作用的药物的组合治疗方案将改善治疗结果。在我们的第一个目标中，我们进行了计算搜索，以确定其他ALDH 2抑制剂。我们介绍了几个改进的计算方法，包括筛选显着更大的图书馆和针对替代网站和构象状态的酶。在第二个目标中，我们通过酶学和生物物理研究表征这些化合物的活性。在我们的第三个目标中，进行一系列体外测定以评估从目标2中出现的最有希望的化合物的药代动力学性质。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，涉及化学合成，生物化学和结构评价以及动物药代动力学和疗效研究。该印第安纳州大学是通过一系列的核心设施，以促进这一进程的独特定位。 公共卫生相关性：线粒体醛脱氢酶（ALDH 2）最常见地与其在酒精代谢中的作用相关，并催化广泛的内源性和生物源性醛至其相应的羧酸的NAD+依赖性氧化。用具有合适的药代动力学性质和功效的小分子抑制ALDH 2可以导致药物治疗剂来帮助治疗酒精依赖。

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.