A new era of GPCR drug discovery: From receptor deorphanization to precision therapeutics.

G protein-coupled receptors (GPCRs) play central roles in the regulation of physiology and disease and constitute the largest family of therapeutic targets. Over the past several decades, GPCR-targeted medicines have transformed the treatment of numerous disorders. A major turning point in the field was the deorphanization of previously uncharacterized receptors, which not only expanded the repertoire of therapeutic targets but also revealed unexpected physiological functions and disease mechanisms. At the same time, advances in molecular and cellular pharmacology have demonstrated that GPCR signaling is far more complex than originally envisioned. Receptor responses are shaped by cellular context, signaling networks, transcriptional regulation, and temporal and spatial dynamics, resulting in diverse physiological and pathological outcomes. More recently, innovations in structural biology, computational science, artificial intelligence, and systems biology have accelerated target identification and therapeutic design. Together, these advances are transforming GPCR drug discovery from traditional screening approaches toward a systems-level understanding of disease biology and precision therapeutic intervention. This review summarizes the historical evolution of GPCR drug discovery, highlights major conceptual breakthroughs that have reshaped the field, and discusses future opportunities and challenges that may define a new era of GPCR drug discovery.