Antioxidative Potential of 3-Methoxyluteolin: Density Functional Theory (DFT), Molecular Docking, and Dynamics—A Combined Experimental and Computational Study

The current study first describes the antioxidative potential of 3-methoxyluteolin. The experimental result is supported by computational approaches. The studied flavone (IC₅₀ 12.40 µg/mL) was comparable to ascorbic acid in antioxidative activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals (IC₅₀ 11.38 µg/mL). From DFT (density functional theory) calculations, its principal radical mechanism in gas and lipid was the FHT (formal hydrogen transfer), whereas the SPL-ET (sequential proton loss-electron transfer) was the main way in water. Hydroxyl groups were crucial radical scavenging sites, especially at carbon C-4′. Kinetic evidence indicated that the reactions between the studied compound with HOO˙ radicals resulted in the k_overall (overall rate constant) of 2.5 × 10⁹ and 1.07 × 10³ (M s)⁻¹ in water and pentyl ethanoate, respectively. The studied molecule also chelated to Zn metal ion to form Zn(3-methoxyluteolin)₂ complex with the lowest binding energy value of −322.911 kcal/mol. Considering the neurodegenerative inhibitory potentials of the studied compound, molecular docking results revealed that 3-methoxyluteolin interacted with the active sites of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the binding affinities of −9.493 and −8.812 kcal/mol, respectively, which are stronger than the reference compound tacrine. To assess the structural stability and binding interactions with each studied protein, molecular dynamics simulations were conducted. The results indicated that the 3-methoxyluteolin complexes with AChE and BChE remained stable during a simulation period.