GPCR Homology Model Development and Application

G-protein-coupled receptors (GPCRs) are a very important class of proteins for drug discovery. Exciting progress has been made recently in the determination of X-ray crystal structures. However, despite this, structural coverage of the receptor family is still thin. We lack direct structural knowledge of many important subfamilies, we have only modest detail of the conformational changes associated with receptor activation and we lack robust crystallographic systems for the rapid determination of ligand binding modes. As a consequence, the ability to build and apply homology models for drug discovery at these targets is very valuable. The accuracy of the models has improved in parallel with the increase in available structural data and the models have been successfully applied to a wide range of lead generation and optimization problems. Keywords: 7TM; adhesion; allosteric; binding sites; drug design; family A; family B; family C; frizzled; ligand docking; metabotropic glutamate; orthosteric; pharmacophore modeling; QSAR; rhodopsin; secretin; selectivity; site-directed mutagenesis; surrogate agonist; virtual screening