G protein-coupled receptors (GPCRs) are the most successful membrane-bound drug targets. GPCRs can be modulated by ligands binding to allosteric sites that are distinct from the main site of endogenous molecules. Allosteric modulators (AMs) have the potential to be sustainable medicines by providing better control of on-target dose-related side effects, reduced off-target effects, and pathway selectivity. The recent experimental GPCR-AM complexes show that AMs can bind inside and outside of a GPCR helical core. Of particular interest are previously uncharacterized membrane-facing allosteric sites found in several GPCRs. This structural information offers opportunities for computational methodologies to tackle AM discovery.<br/>We have recently developed a probe-confined dynamic mapping protocol to detect allosteric sites in GPCRs. In this protocol, we combined enhanced sampling molecular dynamics (MD) simulations with a fragment-based approach to map allosteric sites at various locations. The key feature of our protocol is the application of a cylinder-shaped wall potential to allow the movement of probes, i.e., fragment/cosolvent molecules within a defined area of the receptor. This approach has helped to overcome the membrane distortion due to cosolvent diffusion into the membrane and to keep a suitable sampling of probe molecules in the receptor while using small concentrations. Exploration of this protocol for several membrane-facing allosteric sites in retrospective and prospective manners will be presented. To facilitate the characterization of these sites we conducted quantum chemical calculations and standard MD simulations in three lipid compositions estimating the strength of intermolecular interactions. The physicochemical aspects of ligand binding at membrane-facing allosteric sites will be also discussed.

Mapping membrane-facing allosteric sites of GPCRs

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