Chimeric molecular modeling and high throughput screening of GPR17: towards the identification of new ligands

GPR17, a GPCR activated by both uracil nucleotides and cysLTs, molecules that belong to two unrelated classes of universal and phylogenetically ancient signal transmitters involved in a wide variety of biological actions. In models of focal brain ischemia in rodents, GPR17 contributes to damage development and repair with different detrimental or beneficial effects, depending on the ischemia phase and the cell types involved. GPR17 was found to be activated on the adult precursor cells that initiate remyelination in the peri-lesioned area, suggesting a role in the transition between immature and myelinating oligodendrocytes. These data make GPR17 an attractive new target to foster repair not only in stroke but also in demyelinating diseases, such as multiple sclerosis. However, new and highly selective GPR17 ligands are needed to complete its in vitro and in vivo characterization and to develop new GPR17-targeting drugs. To this purpose, GPR17 structure was modeled through a ‘chimeric’ homology modeling procedure, keeping into account all the useful structures of GPCRs proposed in literature. Before checking the quality of our model, it was submitted to a refinement procedure through molecular mechanics. A combined high throughput screening pipeline, consisting of in silico molecular docking followed by in vitro GPR17 activity measurement, helped us select new potent agonists and/or partial agonists, with an activity noticeably higher than that of GPR17 endogenous activators. This integrated approach, that implements in silico and in vitro molecular pharmacology in a unique pipeline, revealed high efficiency in screening large databases (150,000 compounds), and in identifying new positive hits. In vitro and in vivo pharmacology experiments with top-scoring ligands will shed new light on GPR17 role in orchestrating lesion remodeling and repair after CNS damage. The optimization of the selected lead compounds also opens new tangible therapeutic perspectives.