Signalling bias in new drug discovery: detection, quantification and therapeutic impact

Biased ligands of seven-transmembrane receptors (also known as GPCRs), which preferentially activate specific signalling pathways associated with a given seven-transmembrane receptor (GPCR), could have novel therapeutic profiles. Here, the authors discuss which methods may be most appropriate to quantify bias in a drug discovery setting. Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure–activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide.