G-protein-coupled receptor-focused drug discovery using a target class platform approach

In recent years, several large pharmaceutical companies have taken a novel approach to drug discovery biology and chemistry in that they channel their efforts with respect to particular target classes, such as G-protein-coupled receptors (GPCRs), toward dedicated, specialized teams. Benefits of such an organizational structure are the prospects of establishing several target-family-specific experimental techniques and skill sets, thereby enabling a comprehensive functional profiling of drug candidates in different pharmacological respects. In this context, the recently increased number of reports on GPCR ligand-biased signaling has further spurred the efforts in the pharmaceutical industry toward broader biological characterization of the test compounds, for example employing high-content screening to analyze different GPCR ligand-induced signaling pathways. The knowledge of the disease-relevant functional properties of the small molecule GPCR ligands enables target-specific chemical optimization and GPCR-subclass-directed library design. In the case of GPCRs, where little – although at present slowly expanding – structural information on the targets is available, the modeling of GPCR structures crucially depends on biological validation (typically supported by site-directed mutagenesis of the GPCR ligand binding site).In this review, we aim to recapitulate efforts in the pharmaceutical industry to address GPCR-directed drug discovery in a target-class-directed platform approach: establishing GPCR-specific biological assay panels and creating computational chemistry methods for finding and optimizing small molecules modulating the activity of GPCRs.