Our presenters review experimental and analytical approaches for detecting and quantifying allosteric modulators. Moreover, the panelists describe how such methods not only reinforce efforts to understand GPCR allostery, but can be exploited to boost this paradigm of drug action.
Obtaining GPCR subtype-selective drugs has proven difficult since the orthosteric site where the endogenous ligand binds are highly conserved across subtypes. It has become apparent that potentially all GPCRs possess allosteric binding sites that are topographically distinct to the location where the endogenous ligand binds, and are less conserved than orthosteric sites. Targeting such allosteric sites with allosteric modulators has several advantages over orthosteric drug discovery because there is a higher likelihood of attaining drug selectivity. Allosteric modulators also offer the potential for “fine tuning” of normal physiological signaling because they still allow for the endogenous agonist to bind to the receptor.