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

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• G protein-coupled receptor 17 (GPR17) is implicated in neurodegenerative diseases and neural repair.
• GPR17 presents a potential therapeutic target for neurological conditions.

Purpose of the Study:

• To identify novel antagonists for GPR17.
• To explore nucleotide-inspired derivatives as potential GPR17 modulators.

Main Methods:

• Structure-guided prioritization of a focused library of 130 nucleotide derivatives using molecular docking.
• Synthesis of selected candidate compounds.
• Evaluation of binding affinity using Grating-Coupled Interferometry (GCI).
• Assessment of functional antagonism via [35S]-GTPγS binding assays.

Main Results:

• Four compounds, including 8-methylamino inosinic acid and three N2-alkyl/acyl-2',3'-O-isopropylideneguanylic acids, were selected.
• Synthesized compounds exhibited nanomolar binding affinities, comparable to Cangrelor.
• All tested compounds demonstrated GPR17 antagonist activity.
• N2-octyl-, N2-butyryl-, and N2-undecanoyl-2',3'-O-isopropylideneguanylic acids displayed the highest potency.

Conclusions:

• An integrated computational and experimental approach successfully identified potent GPR17 antagonists.
• The findings provide a basis for rational drug design targeting GPR17.
• These novel antagonists hold promise for therapeutic applications in neurodegenerative disorders and neural repair.