Pharmacophore-based approach for identifying compounds with myricetin-like pharmacophoric features as potential GSK3β inhibitors in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with the hyperactivity of glycogen synthase kinase-3 beta (GSK3β). Myricetin is a potent GSK3β inhibitor but also associated with low oral bioavailability, poor absorption, and rapid degradation in the gastrointestinal tract. This study aims to identify novel compounds with myricetin-based pharmacophoric features as potential GSK3β inhibitors using in-silico approaches. A pharmacophore model based on myricetin’s interactions with GSK3β was generated to screen the ZINCPharmer database, and molecular docking was conducted using PyRx software. DFT was carried out using Gaussian atomic and molecular structure system. The top four compounds, ZINC03257086, ZINC13477129, ZINC15015398, and ZINC59501909, demonstrated favourable predicted binding energies of − 10.4, − 10.2, − 10.6, and − 10.2 kcal/mol, respectively. Their drug-likeness, oral bioavailability, physicochemical properties and target prediction were favourable, as assessed by the SwissADME and SwissTargetPrediction webserver, while ADMET properties evaluated via pkCSM, LogBB_Pred and Protox-3.0 predicted high blood–brain barrier permeability and comparatively favourable toxicity profile, especially for ZINC59501909. Structural alignment through Pharmagist confirmed structural congruence among the hits. Molecular dynamics simulations using Desmond suggested dynamically maintained interactions of these compounds, maintaining critical amino acid interactions (hinge and conserved catalytic sites) essential for GSK3β inhibition. Consistent with the DFT analysis, ZINC59501909 exhibited favourable qualitative electronic characteristics among the identified hits. These findings underscore the promise of the selected compounds identified through the myricetin-GSK3β based pharmacophore model, especially ZINC59501909, as potential lead compounds for GSK3β inhibition in the context of AD, warranting further in vitro and in vivo studies to confirm their efficacy.