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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

基本信息

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
项目类别：
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

项目摘要

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）失调有助于精神健康障碍，包括主要的抑郁症（MDD）、双相情感障碍（BD）和季节性情感障碍（SAD）。褪黑激素与CR密切相关，但尽管多年的研究，许多问题，关于它的作用以及它如何影响情绪。褪黑激素合成的限速步骤涉及酶曲马多宁-N-乙酰转移酶（SNAT，AANAT）。SNAT的抑制将是这是一种研究褪黑激素生理功能的有价值的方法，可用于治疗诸如SAD等涉及异常高褪黑激素的疾病。已发表的抑制剂细胞渗透性、选择性和/或效力的问题，这些问题阻碍了进展到人体试验该项目的目的是1）鉴定有效的，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。细胞渗透性SNAT抑制剂。为了实现目标1，我们将使用一个更生理相关的 SNAT的结构比过去一直使用的，绑定到它的伴侣上，具有更封闭的结合位点，我们假设这将有更大的预测性比以前的模型，在ZINC数据库中筛选商业化合物。作为选择性过滤器，我们将停靠具有针对抗靶标的预测SNAT结合的高分的商业化合物，褪黑激素受体1和2（MT1 - 2），我们还将优先考虑计算的属性，具有细胞渗透性。从这次虚拟筛选活动中选出的前200种化合物将是购买后，将根据分层进展计划评估体外活性。在酶测定中具有良好效力的化合物（Ki <10 µ M）将被推进到PAMPA，评估渗透性，然后MT1 - 2受体测定选择性。概念验证功效在斑马鱼幼鱼中的研究将提供一种有效和经验证的方法来评估SNAT抑制在一个生命系统中。在目标2中，我们将使用我们的模型来设计新的支架，现有的几种药物样SNAT抑制剂。此外，我们扩大了一个创新的，但不够研究了通过其烷基转移酶活性在SNAT的活性位点形成抑制剂的策略。强有力的动力学机制方法和共晶结构的选择抑制剂将是用于开发更完整的SNAT抑制模型，这将是非常有影响力的用于研究和治疗CR疾病。