Scalable technologies for illuminating the druggable GPCR-ome

产品说明：G蛋白偶联受体（GPCR）代表了人类基因组中最大的一类信号受体，也是治疗药物靶向最多的家族。响应于从质子到生物胺到脂质到趋化因子的配体，它们对药物发现的吸引力反映了它们所识别的信号的重要性，并且随着它们的结构的确定，它们结合位点的内在配体能力变得显而易见。尽管有强烈的兴趣，但大多数GPCR仍然很少有化学物质的注释。在这项拨款中，我们将采取双管齐下的方法来克服这些困难。在具体目标1中，我们将在酵母和哺乳动物细胞中开发和验证可扩展的检测方法，以筛选5321种药物和试剂的库。在具体目标2中，我们将开发和验证可扩展的计算屏幕对孤儿GPCR的建模结构，利用经验命中。到项目结束时，我们预计将对30个孤儿GPCR进行验证和物理筛选，并为20个孤儿GPCR生产计算优化的铅样化合物。

DESCRIPTION: G-Protein Coupled Receptors (GPCRs) represent both the largest class of signaling receptors in the human genome and the family most targeted by therapeutic drugs. Responding to ligands that vary from protons to bioamines to lipids to chemokines, their attractiveness for drug discovery reflects the importance of the signals they transduce and, as has become apparent with the determination of their structures, the intrinsic ligand- ability of their binding sites. Despite intense interest, most GPCRs remain sparsely annotated by chemical matter. In this grant we will take a two-pronged approach to overcome these difficulties. In Specific Aim 1 we will develop and validate scalable assays in yeast and mammalian cells with which to screen a library of 5321 drugs and reagents. In Specific Aim 2 we will develop and validate scalable computational screens against modeled structures of the orphan GPCRs, leveraging the empirical hits. By the end of the project period we anticipate validating and executing physical screens against 30 orphan GPCRs and producing computationally optimized lead-like compounds for 20.