Molecular Details of Psychoactive Drug Actions

精神活性药物作用的分子细节

• 批准号: 10557802
• 负责人: Bryan L. Roth
• 金额: $ 61.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-06 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557802
• 关键词: Acceleration; Agonist; Anxiety; Arrestins; Binding; Characteristics; Chemicals; Complex; Coupling; Cryoelectron Microscopy; Development; Disease; Docking; Drug Interactions; Drug Targeting; Drug usage; Eating Disorders; Enzymes; Essential Drugs; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Grant; HTR2A gene; Hydrophobicity; Investigation; Ion Channel; Libraries; Ligands; Membrane Proteins; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Conformation; Mutagenesis; Obesity; Pattern; Pharmaceutical Preparations; Phosphorylation; Property; Protein Isoforms; Psychoses; Psychotropic Drugs; RNA Editing; Research; Resolution; Schizophrenia; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Site; Site-Directed Mutagenesis; Sleep Disorders; Structure; Tail; Testing; Transducers; antagonist; atypical antipsychotic; autism spectrum disorder; design; drug action; drug-like compound; improved; innovation; insight; molecular modeling; neuropsychiatric disorder; new technology; novel; novel therapeutics; programs; receptor; receptor binding; serotonin receptor; severe mental illness; small molecule libraries; tool

PROJECT SUMMARY: Scientific summary: The 5-HT2-serotonin family of receptors represents essential drug targets for most atypical antipsychotics as well as drugs useful in treating obesity, sleep disorders, psychosis and autistic- spectrum disorders. It is currently unknown how these drugs interact with their target receptors. Here we aim to obtain high resolution structures of 5-HT2-family receptors bound to various transducers (G proteins and arrestins) and biased and unbiased agonists. We will use these structures to prosecute ultra-large-scale docking campaigns (up to 15 billion novel compounds) to discover improved chemical tools for these receptors. These studies are both innovative technically and conceptually by providing an unprecedented understanding of the molecular and atomic details responsible for psychoactive drug actions. Additionally, models which attempt to explain ligand-specific properties of biased signaling from the perspective of ligand-receptor interactions will be tested by a combination of direct structural studies, molecular modeling, docking, site-directed mutagenesis and functional studies. We anticipate that our studies will reveal key ligand-receptor interactions essential for biased signaling for serotonin receptors. Elucidating the molecular details for such interactions provides a template for the structure-guided design of novel therapeutics.

项目概要： 科学总结： 5-HT2-血清素受体家族代表了大多数非典型患者的基本药物靶点 抗精神病药以及可用于治疗肥胖、睡眠障碍、精神病和自闭症的药物 频谱障碍。目前尚不清楚这些药物如何与其靶受体相互作用。这里 我们的目标是获得与各种传感器结合的 5-HT2 家族受体的高分辨率结构（G 蛋白和视紫红质抑制蛋白）以及有偏和无偏激动剂。我们将利用这些结构来起诉 超大规模对接活动（多达 150 亿种新化合物）以发现改进的化学物质 这些受体的工具。 这些研究在技术和概念上都具有创新性，提供了前所未有的 了解导致精神活性药物作用的分子和原子细节。 此外，试图解释偏向信号传导的配体特异性特性的模型 配体-受体相互作用的观点将通过直接结构研究的结合来测试， 分子建模、对接、定点突变和功能研究。我们预计 我们的研究将揭示对血清素偏向信号至关重要的关键配体-受体相互作用 受体。阐明这种相互作用的分子细节提供了 新型疗法的结构引导设计模板。