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Discovery of Effective Gsk-3Β Inhibitors As Therapeutic Potential Against Alzheimer's Disease: A Computational Drug Design Insight Publisher Pubmed



Asl FSS1 ; Malverdi N2 ; Mojahedian F3 ; Baziyar P4 ; Nabiafjadi M3
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Source: International Journal of Biological Macromolecules Published:2025


Abstract

Alzheimer's disease (AD) is mostly thought to be caused by overactivity of glycogen synthase kinase 3-beta (GSK3-β). Therefore, a GSK-3β inhibitor may be a suggested medicine for Alzheimer's therapy. Nowadays, computational techniques are thought to be among the quickest and most affordable options for therapeutic design and drug discovery. Following a preliminary screening of flavonoids for possible protection against cognitive illnesses such as Alzheimer's, Amentoflavone, Curcumin, and Notopterol were shown to be promising candidates. Using molecular docking, the ligand orientation and binding energy in the ATP-binding pocket of GSK-3β were ascertained. Amentoflavone formed a hydrogen bond with the GSK-3β protein's ATP binding site during the molecular docking phase, obtaining the highest negative binding energy. However, when the results moved closer to a molecular dynamics simulation, the findings changed, and Curcumin was shown to be the most potent inhibitor. All structures remained stable during the MD simulation of the GSK-3β protein and its ligands. Moreover, compared to other natural compounds, Curcumin showed higher binding free energy. Therefore, Curcumin may be useful as a polyphenolic flavonoid in the prevention and treatment of AD. Hence, additional research in vitro and in vivo can focus on these flavonoid compounds as an alternative treatment. © 2025 Elsevier B.V.
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