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.