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Conformational challenges of GPCR drug discovery​

G-protein coupled receptors (GPCRs), seven-transmembrane domain receptors, constitute a large protein family of proteins that sense molecules outside the cell and activate inside signal transduction pathways and cellular responses.


Traditionally, GPCRs were considered as simple switches that can be turned on or off. Accordingly, a GPCR ligand was classified simply as an agonist, an antagonist or an inverse agonist based on the biological response to the compound.However, it is becoming evident now that therapeutic compounds bind to and stabilize different GPCR conformations, which in turn promote opposite effects on diverse intracellular signaling pathways involving different G proteins, receptor kinases, arrestins or other adaptor proteins.

Figure 1: Conformational complexity of GPCR transmembrane signaling. Schematic representation of ligand-biased efficacy, where three different ligands (L1, L2, L3) stabilize different druggable receptor conformations that trigger separate effector pathways leading to divergent biological/therapeutic responses.


For many diseases, it is now realized that the pathological phenotype is caused by the aberrant modulation of only one of these signalling pathways. Accordingly, the disordered pathway efficacy can only be restored by therapeutics that stabilize the correct target conformation only (the druggable conformation only) to revert disease status or slow down disease progression with fewer side effects.