Next generation GPCR drug discovery

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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.