Application of comparative modelling to the design and discovery of novel GPCR ligands

This Ph.D. project was mainly focused on the building and validation of the three-dimensional structures of G protein-coupled receptors and on the assessment of their reliability and usefulness in the drug design process. Different GPCRs have been extensively investigated, for which X-ray crystal structures were either available or not: the MT1 and MT2 melatonin receptors, the 5-HT2C serotonin receptor, the H3 histamine receptor, the beta2 adrenergic receptor and the A2A adenosine receptor. A number of different computational techniques were applied to build and refine the receptor 3D coordinates, to characterize the ligand recognition process at a molecular level and to evaluate the main receptor rearrangements occurring upon ligand binding. This study threw light on the role of GPCR crystal structures and homology models in the current medicinal chemistry landscape, highlighting their usefulness for the characterization of the ligand recognition mechanism at a molecular level.