Drug abuse: Discovering ligands for pertinent GPCRs

描述（由申请人提供）：分子文库筛选中心网络（MSLCN）由美国国立卫生研究院创建，作为国家资源，具有以下目标：(1)提供高通量筛选（HTS）能力，以识别在生物分析中活跃的小有机分子（先导化合物）；(2)将合成化学工具应用于这些先导物，以提高它们作为研究体外和体内生物系统的探针的效用；(3)将化合物和相关信息作为研究工具提供给公共和私营部门。这些信息可以在PubChem数据库中访问。该项目的一个战略重点是对不同基因家族中的蛋白质类别实施基于高温热成像的检测。为此，我们提出以下建议：1 .根据MLSCN RFA-RM-04-017中详细的指令，建立杜克大学分子文库筛选中心（DMLSC）作为MLSCN的一个完整的卫星成员。我们的主要重点领域将是孤儿所代表的基因家族，并鉴定出7个跨膜/G蛋白偶联受体（7TM/GPCR）及其相应的调节蛋白。我们将使用杜克大学科学家发明并获得专利的一种高含量成像技术作为我们的初级HTS。在这个主题结构中，我们有以下目标：(a)在第一年第三季度发展每周处理10,000种化合物的能力，从而在第四季度末达到每年10次或更多的检测量；(b)在项目第二年第一季度末具有在两周内每次检测处理100,000种化合物的能力；(c)在项目第三年第一季度结束时，具备每2-2.5周处理100,000种化合物进行单独分析的能力；(d)开发补充能力，根据NIH指南及时将相关分析数据（包括描述先导化合物的信息）上传到PubChem。通过实现这些目标，杜克筛选中心将超过NIH的检测吞吐量目标，即每年通过20次单独的检测筛选100,000种化合物，并将化合物和信息作为研究工具提供给公共和私营部门。

DESCRIPTION (provided by applicant): The Molecular Libraries Screening Center Network (MSLCN) has been created by the NIH to serve as national resource with the following objectives: (1) To provide High Throughput Screening (HTS) capability to the problem of identifying small organic molecules (lead compounds) that are active in biological assays, (2) To apply the tools of synthetic chemistry to these leads in order to improve their utility as probes for studying biological systems both in vitro and in vivo, and (3) To make the compounds and associated information available to the public and private sectors as research tools, the information being accessible in a database to be known as PubChem. A strategic focus of the project is implementing HTS-based assays for classes of proteins within different gene families. To this end, we propose the following: I. To establish in accordance with the directives detailed in the MLSCN RFA-RM-04-017, a Duke University Molecular Libraries Screening Center (DMLSC) as an integral satellite member of the MLSCN. Our primary areas of focus would lie with the gene families represented by the orphan and identified Seven Transmembrane/G protein coupled receptors (7TM/GPCR) and their corresponding regulatory proteins. We would use for our primary HTS a high content imaging technology invented and patented by Duke Scientists. Within this thematic structure we have the following aims: (a) To develop the capability by the third quarter of Year 1 to process 10,000 compounds per week enabling a throughput of 10 or more assays per year by the end of the fourth quarter, (b)To have the capability by the end of the first quarter of Year 2 of the project to process 100,000 compounds per assay in two weeks, (c) To have the capability by the end of the first quarter of Year 3 of the project to process 100,000 compounds for separate assays every 2-2.5 weeks and (d) To develop the complementary capability to upload the associated assay data, including information describing lead compounds, to PubChem in a timely manner consistent with NIH guidelines. By accomplishing these aims a Duke screening Center will exceed the NIH assay throughput goal of screening 100,000 compounds in 20 separate assays per year and the associated goal of making compounds and information available to the public and private sectors as research tools.