Molecular glues as GPCR modulators: unveiling three distinct mechanistic pathways for signal regulation

Abstract

G protein-coupled receptors (GPCRs) constitute a large and pharmaceutically significant family of membrane proteins that mediate a wide range of physiological responses. Conventional modulation strategies primarily target orthosteric sites, but recent studies have identified a novel class of modulators known as 'molecular glues' that stabilize specific receptor-transducer interfaces. This review categorizes molecular glues into three mechanistic groups on the basis of their mode of action: those that directly stabilize receptor-transducer complexes, those that induce biased signaling through allosteric interactions, and those that modulate signaling indirectly by targeting allosteric regulatory sites. With advances in structural biology and computational methodologies, molecular glues are increasingly recognized as promising biased agonists, next-generation therapeutic agents, and valuable chemical tools for elucidating GPCR signaling pathways.

Keywords: Biased signaling; G protein-coupled receptors (GPCRs); Intracellular allosteric site; Molecular glues.