Serotonin N-Acetyl-Transferase Inhibitors for Circadian Rhythm Disorders

血清素 N-乙酰转移酶抑制剂治疗昼夜节律紊乱

• 批准号: 10522741
• 负责人: Allen Thomas
• 金额: $ 39.48万
• 依托单位: UNIVERSITY OF NEBRASKA KEARNEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522741
• 关键词: Acetyltransferase; Active Sites; Animals; Arylalkylamine N-Acetyltransferase; Behavioral Model; Binding; Binding Sites; Biological Assay; Bipolar Disorder; Brain; Cells; Chemicals; Circadian Rhythm Disorder; Circadian Rhythm Sleep Disorders; Circadian Rhythms; Clinical; Coenzyme A; Collaborations; Computer Models; Crystallization; Databases; Diphosphates; Disease; Docking; Enzymatic Biochemistry; Enzymes; Future; Goals; Hour; Human; In Situ; In Vitro; Institutes; Kinetics; Larva; Lead; Major Depressive Disorder; Mediating; Melatonin; Melatonin Receptors; Mental Health; Mental disorders; Mentors; Methods; Modeling; Molecular Chaperones; Mood Disorders; Moods; Motor Activity; Organism; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phototherapy; Physiological; Property; Publishing; Research; Rhodanine; Role; Scheme; Seasonal Affective Disorder; Serotonin; Site; Sleep; Sleep Disorders; Structure; Sulfhydryl Compounds; Testing; Training; Transferase; Visit; Visual impairment; Work; Writing; X-Ray Crystallography; Zebrafish; alkyltransferase; base; clinical candidate; computerized tools; counterscreen; design; drug candidate; efficacy study; enzyme mechanism; experience; improved; in silico; in vitro activity; in vitro testing; in vivo; inhibitor; innovation; interest; lead optimization; medical schools; meetings; novel therapeutics; prevent; rational design; receptor; scaffold; screening; simulation; tryptamine analog; undergraduate student; virtual; virtual screening

Circadian rhythm (CR) dysregulation contributes to mental health disorders, including major depressive disorder (MDD), bipolar disorder (BD), and seasonal affective disorder (SAD). Melatonin has been strongly associated with CR, but despite years of research, many questions remain regarding its role and how it influences mood. The rate-limiting step in melatonin synthesis involves the enzyme serotonin-N-acetyltransferase (SNAT, AANAT). Inhibition of SNAT would be a valuable approach for studying the physiological function of melatonin and could be used to treat disorders such as SAD that involve abnormally high melatonin. Published inhibitors have problems with cell permeability, selectivity, and/or potency, which have prevented advancement to testing in humans. The aims of this project are 1) to identify potent, selective and cell permeable SNAT inhibitors by virtual screening, and 2) to use structure-guided design to improve potency of cell permeable SNAT inhibitors. To achieve Aim 1, we will use a more physiologically relevant SNAT structure than has been used in the past, bound to its chaperone, with a more closed binding site, which we hypothesize will have greater predictability than previous models for screening commercial compounds in the ZINC database. As a selectivity filter, we will dock commercial compounds with high scores for predicted SNAT binding against the anti-targets, melatonin receptor 1 and 2 (MT1-2), We will also prioritize by calculated properties that correlate with cell permeability. The top 200 compounds from this virtual screening campaign will be purchased, and in vitro activity will be evaluated according to a tiered progression scheme. Compounds with good potency in an enzyme assay (Ki < 10µM) will be advanced to PAMPA for assessing permeability, and then MT1-2 receptor assays for selectivity. Proof-of-concept efficacy studies in zebrafish larvae will provide an efficient and validated way to evaluate SNAT inhibition in a living system. In Aim 2, we will use our model to design new scaffolds based on one of the few existing drug-like SNAT inhibitors. Also, we expand upon an innovative but insufficiently studied strategy for forming inhibitors at SNAT’s active site via its alkyltransferase activity. Powerful kinetic mechanism methods and co-crystal structures of selected inhibitors will be employed to develop a more complete model of SNAT inhibition, which would be highly impactful for studying and treating CR disorders.

昼夜节律（CR）失调会导致心理健康障碍，包括主要 抑郁症（MDD），躁郁症（BD）和季节性情感障碍（SAD）。 褪黑激素与CR密切相关，但是目的地多年研究，许多问题 保持其角色及其影响情绪的影响。褪黑激素合成的速率限制步骤 涉及酶5-羟色胺-N-乙酰转移酶（SNAT，AANAT）。抑制SNAT将是 研究褪黑激素的物理功能的宝贵方法，可以用来 治疗涉及异常高的褪黑激素的SAD之类的疾病。已发表的抑制剂具有 细胞渗透性，选择性和/或效力的问题，这已经阻止了进步 在人类中进行测试。该项目的目的是1）确定潜力，选择性和细胞可渗透 通过虚拟筛选进行SNAT抑制剂，以及2）使用结构引导的设计来提高 细胞渗透的SNAT抑制剂。为了实现目标1，我们将使用更加相关的 SNAT结构比过去使用的结构比其伴侣绑定，更封闭 与以前的模型相比 筛选锌数据库中的商业化合物。作为选择性过滤器，我们将停靠 具有高分的商业化合物预测SNAT与抗目标的结合， 褪黑激素受体1和2（MT1-2），我们还将通过相关的计算属性确定优先级 具有细胞渗透性。该虚拟筛选活动中的前200个化合物将是 购买，并将根据分层进展方案评估体外活性。 在酶测定中具有良好效力的化合物（Ki <10µm）将被提升到PAMPA 评估渗透性，然后评估MT1-2受体分析的选择性。概念证明效率 斑马鱼幼虫的研究将为评估SNAT抑制作用提供有效且经过验证的方法 在AIM 2中，我们将使用模型根据其中一个设计新的脚手架 现有的类似药物的SNAT抑制剂。另外，我们扩展了一种创新但不足 通过其烷基转移酶活性在SNAT活性部位形成抑制剂的策略。 选定抑制剂的强大动力学方法和共结构结构将是 被用来开发更完整的SNAT抑制模型，这将是很大的影响力 用于研究和治疗CR障碍。