Accelerating the orphan GPCR pipeline: GPR149 as a case study in dual-domain target validation

High failure rates in drug development for central nervous system (CNS) and metabolic diseases frequently stem from a lack of knowledge about their selected drug targets. With unknown ligand chemistry, orphan G-protein-coupled receptors (GPCRs) represent high-risk, but high-potential, high-reward opportunities for pharmaceutical development. Here, I describe a framework for de-risking such targets using GPR149 as a prototype. The Four-Pillar Framework, combining high-throughput screening, cryo-electron microscopy (EM), artificial intelligence (AI)-driven chemistry, and parallel circuit validation, unexpectedly revealed the dual metabolic (weight loss) and CNS applications of GPR149. In the process, a seemingly intractable orphan receptor has become a development asset with blockbuster potential. This methodology offers a reproducible template for exploring the 'dark GPCRome', particularly for disorders in which metabolic dysfunction and CNS comorbidities co-present in real-world patient populations.