Strategies for designing GPCR-focused libraries and screening sets.

: In recent years drug discovery has progressively moved away from a traditional single-target focus toward a family-based approach. The development of knowledge relating to targets and ligands of the same protein family has been actively pursued to support more predictive and efficient pharmaceutical research. The design of focused libraries and screening sets for the G protein-coupled receptor (GPCR) family has been undertaken along several different routes. A first approach has been ligand-based, relying either on physicochemical properties or on privileged substructures of GPCR ligands, but despite some success this approach has suffered from the near absence of knowledge coming from the receptor. To strengthen the weak link between the chemical and biological aspects, new databases have been developed and have steadily moved toward integrated information systems. Several research groups have reported novel approaches to library design and compound selection based on two- or three-dimensional mapping of the ligand-receptor interaction sites. The development of homology models derived from the rhodopsin crystal structure, the use of site-directed mutagenesis in relation to ligand structure-activity relationships (SARs), and the integration of informatics analyses have been critical elements for driving new designs in a modern chemogenomics environment.