Molecular Details of Psychoactive Drug Actions

项目概要： 科学总结： 5-HT 2 - 5-羟色胺受体家族代表了大多数非典型性 抗精神病药以及用于治疗肥胖、睡眠障碍、精神病和自闭症的药物， 谱系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-HT 2家族受体的高分辨率结构（G 蛋白质和抑制蛋白）和偏向性和非偏向性激动剂。我们将利用这些机构起诉 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是创新的，提供了前所未有的 了解负责精神药物作用的分子和原子细节。 此外，试图解释配体特异性的偏置信号传导的模型， 配体-受体相互作用的观点将通过直接结构研究的组合进行测试， 分子建模、对接、定点诱变和功能研究。我们预计 我们的研究将揭示关键的配体-受体相互作用对5-羟色胺的偏向信号至关重要 受体。阐明这种相互作用的分子细节提供了 结构导向设计新疗法的模板。

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.