Structure-based Virtual Screening for Ligands of G Protein-coupled Receptors
Due to the vast implications of their signalling, G protein-coupled receptors play a very important role in the pharmaceutical sector. Thanks to the progress recently made in the field of structural determination, structure-based virtual screening for ligands of G protein-coupled receptors is becoming an increasingly more adopted practice, as it can focus the lead discovery process with conspicuous savings of time and money. Controlled experiments and actual screening campaigns have shown that the crystal structures of the receptors are indeed applicable to structure-based virtual screening leading, with the testing of a only few dozens of molecules, to the identification of several novel and diverse hit compounds amenable to further optimization through medicinal chemistry. Moreover, despite that fact that all the X-ray structures of GPCRs solved at the time of writing have been obtained in complex with either inverse agonists or neutral antagonists, actual virtual screening campaigns and controlled experiments have demonstrated the possibility of biasing the screens towards the selective retrieval of agonists or blockers. Besides directly offering platforms for the virtual screens, experimental GPCR structures also provide templates for the constructions of homology models of other members of the superfamily. In this case, controlled experiments and actual campaigns have also undoubtedly demonstrated that such models can indeed be successfully applied to structure-based virtual screening.