Multiplexed Measurement of Psychoactive Drug Selectivity Profiles

项目摘要 这项第二阶段建议的主题是完成中枢神经系统GPCR筛查小组- 相关受体，使发现作用于多个GPCR靶点的候选治疗药物成为可能。 大多数内源性GPCR配体激活多个受体。这些配体具有生物功效。 通过“选择性非选择性”；由此激活一小部分受体以改变 按特定的配基递增。同样，许多治疗神经性和物质滥用的有效药物 紊乱之所以有效，只是因为它们调节了多个靶点。不幸的是，目前的药物 发现技术一次只允许发现一个受体，有效地留下任何 对Chance有利的“非靶点”受体相互作用。为了有目的地识别 为了调节多个感兴趣的受体，需要一个系统来描述这些反应 同时。在第一阶段的研究中，Primity开发了一种新的GPCR检测和细胞条形码 一种能够在一个微滴度的单井中同时筛选八个GPCR目标的系统 盘子。这项第二阶段的提案将神经疾病小组进一步扩大到54个目标，提供 数十个经过验证的中枢神经系统药物靶点的复合作用的全球视图。所使用的技术 检测GPCR激活将优化高通量筛查，并对数据进行分析 自动化，每天可筛选4,000口井(100,000个数据点)。系统 将以1500种化合物的试点筛选为基准，以确定大规模平行的可行性 GPCR筛查。将目标扩大到54个，同时展示了适当的 本计划书中概述的筛选指标将为商业化提供基础 技术为有目的地发现多效性配体提供了一种新的筛选平台 神经学GPCR靶点。

Project Summary The subject of this Phase II proposal is the completion of a GPCR screening panel for CNS- related receptors, enabling the discovery of therapeutic candidates acting at multiple GPCR targets. Most endogenous GPCR ligands activate multiple receptors. These ligands achieve biological efficacy through a "selective non-selectivity"; whereby a small subset of receptors is activated to varying degrees by a specific ligand. Similarly, many effective drugs for neurological and substance abuse disorders are effective only because they modulate multiple targets. Unfortunately, current drug discovery technologies only permit ligand discovery one receptor at a time, effectively leaving any beneficial "off-target" receptor interactions to chance. In order to purposefully identify compounds that modulate multiple receptors of interest, a system is needed that profiles these responses simultaneously. In Phase I studies, Primity developed a novel GPCR assay and cellular barcoding system that enabled the simultaneous screening of eight GPCR targets in a single well of a microtiter plate. This Phase II proposal further expands the Neurological Disease Panel to 54 targets providing a global view of compound action across dozens of validated CNS drug targets. The techniques used for detecting GPCR activation will be optimized for high-throughput screening, and the data analysis automated, to enable screening of 4,000 wells (>100,000 data points) per screening day. The system will be benchmarked with a pilot screen of 1500 compounds to establish feasibility of massively parallel GPCR screening. The extension of targets to 54, coupled with the demonstration of the appropriate screening metrics outlined in this proposal, will provide the foundation for commercializing this technology as a novel screening platform for the purposeful discovery of pleiotropic ligands for neurological GPCR targets.