Molecular Determinants for GPR55 Activity

GPR55是一种溶血磷脂酰肌醇(LPI)敏感的G蛋白偶联受体(GPCR)，它识别一种亚 一组大麻素CB1和CB2配体。被提议的项目的目标是了解功能 GPR55的特征可能定义药物-受体相互作用的机制 病理生理功能，包括药物滥用。GPR55被认为与炎性疼痛有关， 神经性疼痛，代谢紊乱，骨骼和神经发育，以及癌症，表明真正的 GPR55配体作为治疗药物的潜力。这些区域中的每一个都具有重要的医学意义 受益于使用选择性激动剂和拮抗剂进行进一步研究。而选择性激动剂和 已经从许多不同的支架中鉴定出GPR55的拮抗剂，其纳摩尔效价并不低 这种受体的配体已经被证实，也没有开发出一种放射性配体来表征结合。我们 最近发现了第一组对激动剂信号和GPR55重要的GPR55残基 激活。这些信息应该有助于合理设计下一代GPR55配体，使用我们的 进化的分子模型。这项提案的目标是使用基于结构的设计和化学信息学 为选定的支架开发结构-活性关系的工具，导致识别Low 保持高受体选择性的纳米分子配体。我们的目标是发现纳摩尔效力的GPR55配体 使用分子建模、化学信息学、高通量筛选和定点定位相结合的方法 诱变。我们将剖析控制GPR55活性的特定信号通路，并研究 配基偏向。

GPR55 is a lysophosphatidylinositol (LPI)-sensitive G-protein coupled receptor (GPCR) that recognizes a sub- set of cannabinoid CB1 and CB2 ligands. The goal of the proposed project is to understand the functional features of GPR55 that may define mechanisms of drug-receptor interactions relevant to physiological and pathophysiological function, including drug abuse. GPR55 has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone and neurological development, and cancer, indicating the real potential of GPR55 ligands as therapeutics. Each of these areas alone is medically important and each would benefit by the use of selective agonists and antagonists to further studies. While selective agonists and antagonists for GPR55 from a number of diverse scaffolds have been identified, no low nanomolar potency ligands have been confirmed for this receptor, nor is there a radioligand developed to characterize binding. We have recently identified the first set of GPR55 residues important for agonist signaling and for GPR55 activation. This information should aid in the rational design of next generation GPR55 ligands, using our evolving molecular model. The goal of this proposal is to use structure-based design and cheminformatics tools to develop structure-activity relationships for selected scaffolds, leading to the identification of low nanomolar ligands that retain high receptor selectivity. We aim to discover nanomolar potency GPR55 ligands using a combination of molecular modeling, chemoinformatics, high-throughput screening and site directed mutagenesis. We will dissect the specific signaling pathways governing GPR55 activity as well as investigate ligand bias.