权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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，包括重大