Drug Abuse: Discovering Ligands for Pertinent GPCRs

描述(由申请人提供)：该中心向国家药物滥用研究所(NIDA)申请的一个重要目标是促进药物成瘾治疗和预防的新方法的发展。我们建议通过为NIDA研究人员提供使能资源来促进这一战略，这可以加速他们的成瘾研究的进展，包括但不限于发现新的小分子化合物。我们计划的主要焦点是以孤儿和已鉴定的七个跨膜G蛋白偶联受体(GPCRs)为代表的基因家族。在过去的三年里，在NIDA的支持下，我们已经建立了一个包含几乎所有与人类成瘾相关的GPCR的开放阅读框架的cDNA集合，更重要的是，我们已经建立了一个扩展的基于现成细胞的分析库，用于NIDA资助的科学家感兴趣的一半以上的GPCR靶标，目标是快速发展到剩余的细胞分析。我们的努力，正式命名为杜克大学分析中心(DUAC)，已经与NIH/NIDA的化学家和生物学家在其他多个机构进行了联合合作，包括五个正在进行的联合项目，其中包括分子图书馆探针生产中心网络(MLPCN)。为了在目前的水平上继续我们的计划，我们正在寻求作为NIDA P30卓越中心的资金，为期四年。作为一个卓越中心，DUAC将继续站在药物成瘾研究的前沿，这是促进技术和与NIDA其他科学家协同合作的结果。我们工作的主要范围将包括新型工具化合物的鉴定以及在纤维素和体内的表征。我们的具体援助包括：1)开发和维护受体cDNA和细胞分析文库，特别是包含荧光β-抑制素和NIDA GPCR靶标的文库，供NIDA研究人员立即访问。2)根据我们或合作科学家提供的有限文库(1-5,000个化合物)，及时(几天到几周)筛选DUAC的受体靶标。3)建立针对MLPCN的项目，以发现新的工具化合物。这一协作战略应加快识别工具化合物，以确定成瘾的生物学特征，并为药物发现技术方面的合作科学家提供教育资源。

DESCRIPTION (provided by applicant): An important goal of this Center application to the National Institute on Drug Abuse (NIDA) is to foster the development of new approaches for drug addiction treatment and prevention. We propose to facilitate this strategy by providing an enabling resource for NIDA investigators that could accelerate the progress of their addiction research, including but not limited to the discovery of novel small molecule compounds. The primary area of focus of our program is the gene families represented by orphan and identified Seven Transmembrane G protein-coupled receptors (GPCRs). With NIDA support over the past three years we have established a cDNA collection containing the open reading frames for almost all human addiction associated GPCRs, and more importantly an expanding repository of off-the shelf cell-based assays for over half of the GPCR targets of interest to NIDA funded scientists, with a goal of quickly progressing to the remaining cell assays. Our efforts, formalized as the Duke University Assay Center (DUAC), have produced joint collaborations with NIH/NIDA chemists and biologists at multiple other institutions, including five joint ongoing projects that include the Molecular Libraries Probe Production Centers Network (MLPCN). To continue our program at the current level of effort we are seeking funding as a NIDA P30 Center of Excellence for four years. As a Center of Excellence the DUAC would continue to be at the forefront of drug addiction research as a consequence of enabling technology and synergizing collaborations with other NIDA scientists. The primary scope of our work would include the identification and in cellulo and in vivo characterization of novel tool compounds. Our specific alms entail: 1)Development and maintenance of receptor cDNA and cell assay libraries, particularly containing fluorescent beta-arrestins and NIDA GPCR targets, for immediately access by NIDA investigators. 2) Screening in a timely manner (days to weeks turnaround) of receptor targets at DUAC against limited libraries (1-5,000 compounds) provided by us or the collaborating scientists. And 3) Establish projects aimed towards the MLPCN for discovery of novel tool compounds This collaborative strategy should expedite the identification tool compounds to characterize the biology of addiction and provide an educational resource for collaborating scientists in drug discovery technology.