Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery

G-protein-coupled receptors (GPCRs) are a family of cell surface proteins that can sense a variety of extracellular stimuli and mediate multiple signaling transduction pathways involved in human physiology. Recent advances in GPCR structural biology have revealed a relatively conserved intracellular allosteric site in multiple GPCRs, which can be utilized to modulate receptors from the inside. This novel intracellular site partially overlaps with the G-protein and β-arrestin coupling sites, providing a novel avenue for biological intervention. Here, we review evidence available for GPCR structures complexed with intracellular small-molecule allosteric modulators, elucidating drug–target interactions and allosteric mechanisms. Moreover, we highlight the potential of intracellular allosteric modulators in achieving biased signaling, which provides insights into biased allosteric mechanisms.