We focus on therapeutic innovation for neuropsychiatric disorders (addiction, schizophrenia, pain, and opioid tolerance) and cardiometabolic diseases centered on the emerging GPCR targets. Using cryo-EM structural biology, AI-driven drug design, and GPCR biosensor-based screening, we systematically investigate the conformational dynamics, ligand recognition and signaling modulation mechanisms of untapped receptors such as neurotransmitter-related GPCRs and orphan receptors, developing allosteric modulators targeting GPCR dimer interfaces and agonist nanobodies to advance mechanism-based first-in-class drug discovery.