Molecular Glues: A New Approach to Modulating GPCR Signaling Bias

Abstract

G-protein-coupled receptors (GPCRs) transmit an extracellular chemical/biological signal across the cell membrane, stimulating an array of intracellular signaling cascades. Canonically, these extracellular signaling molecules bind to the endogenous ligand pocket (orthosteric pocket), which stabilizes either an active or inactive conformational ensemble of the receptor. However, recent structural evidence indicates that small molecules can mediate the protein–protein interactions between the GPCR and their intracellular transducers. These small molecules are reminiscent of molecular glues and can be powerful tools for modulating GPCR signaling bias. In this Perspective, we will investigate the current structural information available on molecular glues and how they modulate GPCR signaling bias. We also examine the prospects of molecular glues and GPCR drug/probe design.