In silico anti-alzheimer study of phytochemicals from Lamiaceae family through GSK3-β inhibition

Glycogen synthase kinase 3-beta (GSK3-β) is a serine-threonine protease expressed in the brain, and its hyperactivity is considered the underlying cause of Alzheimer’s disease. This enzyme requires an ATP molecule in its N-terminal lobe to phosphorylate its substrates, with the most important substr...

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Bibliographic Details
Published in:Scientific reports 2024-01, Vol.14 (1), p.834-834, Article 834
Main Authors: Zareei, Sara, Pourmand, Saeed, Eskandarzadeh, Marzieh, Massahi, Shokoufeh
Format: Article
Language:English
Subjects:
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Acids
Adenosine Triphosphate
Alzheimer's disease
Apigenin
ATP
Enzymes
Glycogen
Glycogen Synthase Kinase 3
Humanities and Social Sciences
Hyperactivity
Kinases
Lamiaceae
Ligands
Luteolin - pharmacology
Luteolin - therapeutic use
Molecular Docking Simulation
multidisciplinary
Neurodegenerative diseases
Phytochemicals - pharmacology
Phytochemicals - therapeutic use
Protein structure
Rosmarinic acid
Science
Science (multidisciplinary)
Tau protein
Threonine
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Summary:Glycogen synthase kinase 3-beta (GSK3-β) is a serine-threonine protease expressed in the brain, and its hyperactivity is considered the underlying cause of Alzheimer’s disease. This enzyme requires an ATP molecule in its N-terminal lobe to phosphorylate its substrates, with the most important substrate being the Tau protein. This study focuses on the inhibitory mechanism of four naturally occurring compounds—apigenin, luteolin, rosmarinic acid, and salvianolic acid—from the Laminaceae family against GSK3-β. The orientation of the ligands within the ATP-binding pocket of GSK3-β and their binding energy were determined through molecular docking. Additionally, molecular dynamics simulations was conducted to study the conformational changes induced by the ligands in the protein structure. The results showed that apigenin and salvianolic acid achieved deeper parts of the cavity compared to luteolin and rosmarinic acid and formed stable complexes with the enzyme. In the rosmarinic acid complex, the enzyme exhibited the most exposed conformation. On the other hand, luteolin binding caused a small closure of the opening, suggesting a potentially ATP-competitive role. Our results suggest these compounds as lead candidates for the design of GSK3-β inhibitors.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-47069-w