The recent availability of X-ray structures for diverse ligand-bound Family A G protein-coupled receptors (GPCRs) in multiple conformations (inactive form with an antagonist/inverse agonist bound and active form with an agonist bound) now enables rational drug design efforts that have historically been applied to soluble enzyme targets. Here, we review properties of these GPCR binding sites, using a unique combination of calculated physicochemical properties and water energetics (GRID, WaterMap and SZMAP) to provide a new perspective and rational assessment of druggability for each GPCR target binding site. Examples are described from several well-studied enzyme systems to support this advanced structure-based approach to assessing druggability and to contrast their properties with those of GPCRs. Changes in receptor conformations between the GPCR inactive and active forms evident from the protein structures are discussed, yielding important pointers for rational drug design of antagonists and agonists and a better understanding of GPCR activation.
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