Molecular Determinants for GPR55 Activity

GPR 55是一种溶血磷脂酰肌醇（LPI）敏感的G蛋白偶联受体（GPCR），它识别一个亚单位， 一组大麻素CB 1和CB 2配体。该项目的目标是了解功能 GPR 55的特征可能定义了与生理和病理学相关的药物-受体相互作用机制， 病理生理功能，包括药物滥用。GPR 55与炎性疼痛有关， 神经性疼痛、代谢紊乱、骨和神经发育以及癌症，表明真实的 GPR 55配体作为治疗剂的潜力。这些区域中的每一个都是医学上重要的， 受益于选择性激动剂和拮抗剂的使用，以进一步研究。虽然选择性激动剂和 已经鉴定了来自许多不同支架的GPR 55拮抗剂，没有低纳摩尔效力 已经证实了这种受体的配体，也没有开发出放射性配体来表征结合。我们 最近鉴定了第一组对激动剂信号传导和GPR 55重要的GPR 55残基， activation.这些信息应该有助于下一代GPR 55配体的合理设计，使用我们的 进化的分子模型本提案的目标是使用基于结构的设计和化学信息学 工具，以开发选定的支架的结构-活性关系，导致低的识别 保持高受体选择性的纳摩尔配体。我们的目标是发现纳摩尔效力的GPR 55配体 使用分子建模、化学信息学、高通量筛选和定点筛选的组合， 诱变我们将剖析控制GPR 55活性的特定信号通路，并研究 配体偏好

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.