Strategies for the discovery of biased GPCR ligands. Issue 4 (April 2019) - Bermudez, Marcel
Highlights: Biased GPCR modulators provide various therapeutic benefits. The number of newly identified biased ligands is constantly increasing. Understanding underlying receptor mechanisms is key for rational design of biased ligands. Ligand structure extension represents a potential blueprint for biased ligand design. Translation of biased signaling to in vivo models will be essential for drug development. Abstract : G-protein-coupled receptors (GPCRs) represent important drug targets with complex pharmacological characteristics. Biased signaling represents one important dimension, describing ligand-dependent shifts of naturally imprinted signaling profiles. Because biased GPCR modulators provide potential therapeutic benefits including higher efficiencies and reduced adverse effects, the identification of such ligands as drug candidates is highly desirable. This review aims to provide an overview of the challenges and strategies in the discovery of biased ligands. We show different approaches for biased ligand discovery in the example of G-protein-biased opioid analgesics and discuss possibilities to design biased ligands by targeting extracellular receptor regions.