An MLSCN for GPCRs Ion Channels, and Transporters(RMI)

描述(由申请人提供)：G蛋白偶联受体(GPCRs)、离子通道和转运体是密集的基础研究领域，也是已被证实的药物靶点。然而，仍然需要新的工具来更好地了解这些蛋白质在生物系统中的作用，并为发现治疗剂铺平道路。尽管制药公司已经在这些蛋白质上进行了配基发现，但它们的零售产品兴趣往往排除或极大地推迟研究结果的发表，或者只考虑许多可能的靶/小分子相互作用模式中的一种。尽管许多学术和工业实验室对小分子配体产生了浓厚的兴趣，但对于绝大多数GPCRs、离子通道和转运蛋白来说，小分子配体并不存在。在分子图书馆和筛选中心网络(MLSCN)倡议的支持下，研究界有很好的机会开发新的工具来帮助理解这些蛋白质。因此，我们建议建立一个MLSCN筛选中心，专注于研究G蛋白偶联受体、离子通道和转运蛋白的化学工具。我们将使用行业标准的仪器和筛选方法对这些蛋白质进行基于细胞的功能性HTS。我们将进一步提高我们的能力，通过使用新技术来快速发现和表征这些靶点以及它们所属的信号通路/生理系统的新工具，这些新技术将允许对这些蛋白质与其伙伴之间的相互作用进行更多生理相关的询问。我们将开发专业知识、技术和方法来了解和改进通过高温超导发现的小分子的性质，以生产支持基础和翻译研究的工具。范德比尔特大学非常适合支持MLSCN中心，因为它结合了拟议目标领域的基础和工业研究专业知识，致力于翻译和化学生物学，以及在建立和维护高度协作的实验室和核心设施方面的卓越传统。

DESCRIPTION (provided by applicant): G-protein coupled receptors (GPCRs), ion channels, and transporters are areas of intense basic research and are proven drug targets. However, there remains a need for new tools to develop a better understanding of the roles of these proteins in biological systems and to pave the way for discovery of therapeutic agents. Although ligand discovery has been performed on these proteins in pharmaceutical companies, their retail product interests often preclude, or greatly delay, the publication of research findings or consider only one of the many possible modes of target/small molecule interaction. Despite intense interest of multiple academic and industry labs, small molecules ligands do not exist for the vast majority of GPCRs, ion channels, and transporters. The research community, supported by the Molecular Libraries and Screening Centers Network (MLSCN) initiative, has an excellent opportunity to develop novel tools to aid in understanding these proteins. Thus, we propose to develop a MLSCN screening center focused on the generation of chemical tools for the study of G-protein coupled receptors, ion channels, and transporters. We will perform cell-based functional HTS for these proteins using industry-standard instrumentation and screening methods. We will further enhance our ability to rapidly discover and characterize novel tools for these targets and the signaling pathways/physiological systems of which they are a part by using new technologies that will allow more physiologically-relevant interrogation of interactions between these proteins and their partners. We will develop the expertise, technologies, and methods to understand and improve the properties of small molecules discovered through HTS to produce tools to support basic and translational research. Vanderbilt University is well suited to support an MLSCN center due to its combination of basic and industrial research expertise in the proposed target areas, its dedication to translational and chemical biology, and its tradition of excellence in the establishing and maintaining highly-collaborative laboratories and core facilities.