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)失调会导致精神健康障碍，包括 抑郁障碍(MDD)、双相情感障碍(BD)和季节性情感障碍(SAD)。 褪黑素与CR密切相关，但尽管多年来的研究，许多问题 继续关注它的作用以及它如何影响情绪。褪黑素合成中的限速步骤 涉及5-羟色胺-N-乙酰转移酶(SNAT，AANAT)。SNAT的抑制将是 为研究褪黑素的生理功能提供了一种有价值的方法，可用于 治疗像SAD这样的疾病，涉及异常高的褪黑素。已发表的抑制剂已经 细胞渗透性、选择性和/或效力方面的问题，这些问题阻碍了进展 在人体上进行测试。该项目的目标是1)确定有效的、选择性的和细胞渗透性的 通过虚拟筛选SNAT抑制剂，以及2)使用结构指导设计来提高SNAT抑制剂的效力 细胞通透性SNAT抑制剂。为了实现目标1，我们将使用更具生理学意义的 SNAT结构比过去一直使用的，绑定到它的伴侣，具有更封闭的 结合位点，我们假设它将比以前的模型具有更大的可预测性 在锌数据库中筛选商业化合物。作为选择性过滤器，我们将对接 预测与抗靶标的SNAT结合得分高的商业化合物， 褪黑素受体1和2(MT1-2)，我们还将根据计算的相关性质进行优先排序 与细胞渗透性有关。这次虚拟筛选活动中排名前200位的化合物将是 购买，体外活性将根据分级递增方案进行评估。 在酶分析中具有良好效力的化合物(Ki&lt；10微米)将被推进到PAMPA用于 评估通透性，然后检测MT1-2受体的选择性。概念验证效能感 对斑马鱼幼体的研究将为评估SNAT抑制提供一种有效和有效的方法 在一个活生生的系统里。在目标2中，我们将使用我们的模型设计新的脚手架，基于 现有的类药物SNAT抑制剂很少。此外，我们还扩展了一种创新但不够的 研究了通过SNAT的烷基转移酶活性在其活性部位形成抑制剂的策略。 选定的缓蚀剂的强大的动力学机制、方法和共晶结构 用来开发更完整的SNAT抑制模型，这将是非常有影响力的 用于研究和治疗CR障碍。