Drug abuse: Discovering ligands for pertinent GPCRs

描述（申请人提供）：NIH创建了分子文库筛选中心网络（MSLCN），作为国家资源，其目标如下：（1）为识别小有机分子的问题提供高通量筛选（HTS）能力（先导化合物）在生物测定中具有活性，（2）将合成化学的工具应用于这些先导物，以提高它们作为用于研究体外和体内生物系统的探针的效用，及（3）将化合物及相关资料提供予公营及私营机构作为研究工具，而有关资料可在一个名为PubChem的数据库内查阅。该项目的战略重点是对不同基因家族中的蛋白质类实施基于HTS的测定。为此，我们提出以下建议：根据MLSCN RFA-RM-04-017中详述的指令，建立杜克大学分子库筛选中心（DMLSC），作为MLSCN不可或缺的卫星成员。我们的主要关注领域将在于以孤儿为代表的基因家族，并确定了七个跨膜/G蛋白偶联受体（7 TM/GPCR）及其相应的调控蛋白。我们将使用我们的主要高温超导体的高内容成像技术发明和专利的杜克科学家。在这一主题结构中，我们有以下目标：（a）在第一年第三季度之前发展每周处理10，000种化合物的能力，从而在第四季度末之前实现每年10次或更多次化验的吞吐量，（B）在项目第二年第一季度末之前具备在两周内每次化验处理100，000种化合物的能力，（c）在项目第三年第一季度末之前，具备每2-2.5周处理100，000种化合物进行单独化验的能力;（d）发展补充能力，按照国家卫生研究院的指导方针，及时向PubChem上传相关化验数据，包括描述先导化合物的信息。通过实现这些目标，杜克筛选中心将超过美国国立卫生研究院的分析吞吐量目标，即每年在20个单独的分析中筛选100，000种化合物，以及使化合物和信息作为研究工具提供给公共和私营部门的相关目标。

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.