Scalable technologies for illuminating the druggable GPCR-ome

描述：G蛋白偶联受体(GPCRs)是人类基因组中最大的一类信号受体，也是治疗药物最具靶向的家族。对从质子到生物胺、从脂类到趋化因子的各种配体的反应，它们对药物发现的吸引力反映了它们传递的信号的重要性，以及随着其结构的确定而变得明显的是其结合部位的内在配体能力。尽管引起了强烈的兴趣，但大多数GPCR仍然很少用化学物质来注释。在这笔拨款中，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分析方法，用来筛选5321种药物和试剂的文库。在特定目标2中，我们将根据孤立GPCR的建模结构开发和验证可伸缩的计算屏幕，利用经验命中。到项目期结束时，我们预计将针对30个孤立的GPCR验证和执行物理筛选，并为20个生产经过计算优化的类铅化合物。

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.