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 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.