Molecular Details of Psychoactive Drug Actions

项目总结： 科学总结： 5-HT2-5-羟色胺受体家族是大多数非典型肺炎患者的基本药物靶点。 抗精神病药物以及治疗肥胖、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目标受体相互作用。这里 我们的目标是获得与各种转导蛋白(G)结合的5-HT2-家族受体的高分辨率结构 蛋白质和阻滞剂)以及有偏见和无偏见的激动剂。我们将利用这些结构起诉 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 这些感受器的工具。 这些研究在技术和概念上都是创新的，提供了前所未有的 对精神活性药物作用的分子和原子细节的理解。 此外，试图解释有偏信号的配基特定属性的模型 配体-受体相互作用的前景将通过直接结构研究的组合进行测试， 分子建模、对接、定点突变和功能研究。我们预料到 我们的研究将揭示5-羟色胺偏向信号的关键配体-受体相互作用 感受器。阐明这种相互作用的分子细节提供了一种 用于新疗法结构导向设计的模板。

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.