Novel hybrid virtual screening protocol based on pharmacophore and molecular docking for discovery of GSK-3β...

GSK-3β is a member of the GSKs subfamily and plays a major role in the regulation of transcriptional elongation, which has attracted widespread attention as a therapeutic target for AD. In this study, by combining pharmacophore-based virtual screening and kinase inhibition assays, we have successfully identified four small molecules that inhibit GSK-3β activity at micromolar potency. These hit compounds showed drug-like properties according to Lipinski's rule of five and ADMET. An inter-complex interaction study showed that all hit compounds adapted well to the ATP pocket of the GSK-3β protein. Among them, hits 2 and 4 displayed considerable inhibitory activities with IC₅₀ value of 0.74 ± 0.04 μM and 2.32 ± 0.84 μM respectively. Overall, the discovered GSK-3β inhibitors act as new chemical leads to develop improved inhibitors that block the interaction of GSK-3β, and the hybrid virtual screening strategy designed in this study provides an important reference for design and synthesis novel selective GSK-3β inhibitors.