Multiplexed Measurement of Psychoactive Drug Selectivity Profiles

描述(由申请人提供)：这项第二阶段提案的主题是完成中枢神经系统相关受体的GPCR筛查小组，从而能够发现作用于多个GPCR靶点的候选治疗药物。大多数内源性GPCR配体激活多个受体。这些配体通过“选择性非选择性”实现生物功效，即一小部分受体被特定的配体不同程度地激活。同样，许多治疗神经和药物滥用障碍的有效药物之所以有效，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的配体，有效地将任何有益的“非靶标”受体相互作用留给了机会。为了有目的地识别调节多个感兴趣受体的化合物，需要一个同时描述这些反应的系统。在第一阶段的研究中，Primity开发了一种新的GPCR检测和细胞条形码系统，能够在一个微滴定板的单个孔中同时筛选八个GPCR靶标。这项第二阶段的提案将神经疾病小组进一步扩大到54个靶点，提供了数十个经过验证的中枢神经系统药物靶点的化合物作用的全球视角。用于检测GPCR激活的技术将针对高通量筛查和数据分析自动化进行优化，以便能够每天筛查4,000口井(&gt；100,000个数据点)。该系统将以1500种化合物的试点筛查为基准，以建立大规模平行GPCR筛查的可行性。将靶点扩展到54，再加上本提案中概述的适当筛选指标的展示，将为将这项技术商业化，作为有目的地发现神经GPCR靶标的多效性配体的新的筛选平台奠定基础。 与公共卫生相关：神经系统疾病涉及一个复杂的受体网络，具有高度冗余的功能，使得使用传统的“一药一受体”模式很难达到治疗效果。这里描述的系统有助于在广泛的中枢神经系统相关靶点上进行高效的化合物筛选，以识别已知药物的意外活性，并能够发现同时针对多个受体的药物。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Neurological diseases involve a complex web of receptors with highly redundant functions making it difficult to achieve therapeutic efficacy using a traditional 'one drug, one receptor' model. The system described here facilitates highly efficient compound screening across a broad range of CNS- related targets to identify unexpected activities of known drugs and enable the discovery of drugs that simultaneously target multiple receptors.