Next generation GPCR drug discovery

项目摘要/摘要 靶向G蛋白偶联受体(GPCRs)的药物占前100名药物的25%，并使 在食品和药物管理局(FDA)批准的所有药物中，有35%是这样的。GPCRs是完整的膜受体 它将细胞外信号转化为各种细胞内反应。GPCR代表着最大的家庭 由于它们在几乎每个器官系统中的表达，膜上的可及性和 有可能引发几乎每一条信号通路。尽管在药物靶向GPCRs方面取得了相对成功 用于治疗神经和精神疾病，如帕金森氏症、精神分裂症、抑郁症和 毒瘾，寻找副作用减轻的新型神经药物在很大程度上仍然是一个艰巨的挑战。 由于技术有限。因此，开发能够发现小说的技术是至关重要的 副作用最小的化合物，如快速、持久、不上瘾和不致幻的化合物 抗抑郁药。大量研究表明，配体稳定了不同的结构构象 单一受体具有不同的有效性，可导致治疗性信号模式的激活 优势。尽管这些调节剂被认为是治疗进展的关键，但 由于缺乏能够对多样性进行定量分析的技术，发现受到了阻碍 大规模GPCRs的功能构象动力学。因此，我们建议进一步验证和 应用我们基于GPCR构象传感器的专利平台技术，实现实时成像 药效学以确定高通量中的功能选择性gpr靶点。

PROJECT SUMMARY/ ABSTRACT Drugs targeting G-protein coupled receptors (GPCRs) represent 25% of the 100 top grossing drugs and make up 35% of all Food and Drug Administration (FDA) approved drugs. GPCRs are integral membrane receptors which transduce extracellular signals into a variety of intracellular responses. GPCRs represent the largest family of druggable targets due to their expression in nearly every organ system, accessibility on the membrane and potential to elicit almost every signaling pathway. Despite relative success in pharmacologically targeting GPCRs for treating neurological and psychiatric disorders such as Parkinson’s disease, schizophrenia, depression and addiction, the identification of novel neural drugs with alleviated side-effects is still a formidable challenge largely due to limited technology. Therefore, it is critical to develop technology that will enable the discovery of novel compounds with minimal side-effects such as fast-acting and long-lasting nonaddictive and nonhallucinogenic antidepressant drugs. Numerous studies have shown that ligands stabilize distinct structural conformations of single receptors with varying efficacies which can lead to the activation of a signaling pattern of therapeutic advantage. Though these modulators have been suggested to be the key to therapeutic advancement, the path to discovery has been hindered by the lack of technology that permits quantitative analysis of the diverse functional conformation dynamics of GPCRs on a large-scale. Therefore, we propose to further validate and apply our patented platform technology based on GPCR conformer sensors which enables imaging of real-time pharmacodynamics to identify functionally selective GPCR targets in high-throughput.