Structure-Guided Prioritization and Synthesis of New Ligands for GPR17 Receptor

GPR17, a G protein-coupled receptor (GPCR) involved in neurodegenerative and repair processes, represents a promising therapeutic target. In this study, an integrated strategy combining structure-guided prioritization of a focused nucleotide- inspired library with experimental assays was employed to identify new GPR17 antagonists. A library of 130 nucleosides, nucleotides, and related derivatives was prioritized by molecular docking, leading to the selection of four candidates (8-methylamino inosinic acid and N2 -n-octyl-, N2-butyryl- and N2-undecanoyl-2′,3′ -O- isopropylideneguanylic acid). These compounds were synthesized and evaluated using Grating-Coupled Interferometry (GCI), which confirmed nanomolar affinities comparable to the reference antagonist Cangrelor. Functional [35S]GTPγS binding assays demonstrated that all tested compounds act as GPR17 antagonists, with N2 -n-octyl-, N2-butyryl- and N2-undecanoyl-2′,3′ -O-isopropylideneguanylic acids showing the highest potency. This integrated approach, combining computational modeling, targeted synthesis, and experimental validation, provides a solid foundation for the rational design of selective GPR17 ligands and paves the way for future optimization efforts aimed at therapeutic applications in neurodegenerative disorders and neural tissue repair.