HARNESSING THE π-CATION INTERACTION IN RATIONAL DRUG DESIGN: DISCOVERY OF POTENT AND ISOFORM-SPECIFIC GSK-3β INHIBITORS FOR ALZHEIMER’S DISEASE

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The π-cation interaction is a noncovalent bonding between an aromatic ligand and a cationic amino acid residue (protonated Arg or Lys) of a receptor to form strong π-effects, which was first observed in hapten-antibody recognition.1 Rational drug design by taking advantage of π-cation interactions can improve potency and specificity of drug candidates. Glycogen synthase kinase-3β (GSK-3β) hyperphosphorylates over 70% sites on tau proteins in Alzheimer patient's brains and thus is a viable therapeutic target of Alzheimer's disease (AD).2 We recently identified a 6-C-glycosylflavone called isoorientin as a substrate-competitive inhibitor of GSK-3β, capable of alleviating tau hyperphosphorylation and amyloid neurotoxicity for AD.3 We hypothesized that utilization of π-cation interactions in the lead optimization would increase potency and specificity of drug candidates to GSK-3β. New GSK-3β inhibitors containing a 6-C-glycosylflavone scaffold were synthesized based on the computer-aided drug design considering π-cation interactions with GSK-3β. The new analogues were examined against a broad panel of kinases for inhibition and selectivity using enzymatic assays. Anti-tau and anti-amyloid toxicities were assessed in an AD neuronal model. Molecular modeling was applied to elucidate the structure-activity relationship (SAR) responsible for potency and specificity improvements. The new GSK-3β inhibitors exhibited significantly increased potency and specificity to GSK-3β. The most promising inhibitor TFGF18 showed an over 300-fold increased potency (nM level) and distinct GSK-3β isoform-specificity (GSK-3β/GSK-3α = 12-fold) as compared to the parent compound isoorientin. TFGF18 effectively ameliorated tau and amyloid toxicities with low μM potency in cellular assays. SAR analyses and in silico modeling suggested that the π-cation interaction of TFGF18 with Lys183 at the substrate site is critical for GSK-3β inhibition and isoform-specificity. The study provided new insights into GSK-3β drug discovery for AD by harnessing the π-cation interaction in rational drug design.