Allosteric approaches to the targeting of G-protein-coupled receptors for novel drug discovery: a critical assessment.

In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has matured and now represents an increasingly viable approach to drug discovery. This is evident in the fact that allosteric modulators have been reported for every class of GPCR, and several are currently in clinical trials with one drug example approved and launched. The allosteric approach has been highlighted for the potential of identifying highly selective compounds with a minimal propensity to produce adverse effect. While much has been written regarding the promises of this approach, important challenges, caveats, and pitfalls exist that are often overlooked. Therefore, a balanced overview of the field that describes both the promises and the challenges of discovering allosteric modulators of GPCRs as novel drugs is presented.