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Inhibitory Mechanism of Baicalein on Acetylcholinesterase: Inhibitory Interaction, Conformational Change, and Computational Simulation.

ABSTRACT: Alzheimer's disease (AD) is the most prevalent chronic neurodegenerative disease in elderly individuals, causing dementia. Acetylcholinesterase (AChE) is regarded as one of the most popular drug targets for AD. Herbal secondary metabolites are frequently cited as a major source of AChE inhibitors. In the current study, baicalein, a typical bioactive flavonoid, was found to inhibit AChE competitively, with an associated IC₅₀ value of 6.42 ± 0.07 µM, through a monophasic kinetic process. The AChE fluorescence quenching by baicalein was a static process. The binding constant between baicalein and AChE was an order of magnitude of 10⁴ L mol^-1, and hydrogen bonding and hydrophobic interaction were the major forces for forming the baicalein-AChE complex. Circular dichroism analysis revealed that baicalein caused the AChE structure to shrink and increased its surface hydrophobicity by increasing the α-helix and β-turn contents and decreasing the β-sheet and random coil structure content. Molecular docking revealed that baicalein predominated at the active site of AChE, likely tightening the gorge entrance and preventing the substrate from entering and binding with the enzyme, resulting in AChE inhibition. The preceding findings were confirmed by molecular dynamics simulation. The current study provides an insight into the molecular-level mechanism of baicalein interaction with AChE, which may offer new ideas for the research and development of anti-AD functional foods and drugs.

SUBMITTER: Liao Y

PROVIDER: S-EPMC8774682 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The inhibitory activity of hesperetin on polyphenol oxidase (PPO) and their interaction characteristics were investigated using multiple spectroscopic methods and computational simulation. Hesperetin, a mixed inhibitor, reversibly inhibited PPO activity, and its half-maximum inhibitory concentration (IC50) values on monophenolase and diphenolase were 80.8 ± 1.4 μM and 776.0 ± 15.5 μM, respectively. Multivariate curve resolution-alternate least squares (MCR-ALS) analysis suggested PPO interacted with hesperetin and formed PPO-hesperetin complex. Hesperetin statically quenched PPO's endogenous fluorescence, and hydrophobic interactions mainly drove their binding. Hesperetin affected the polarity of the microenvironment around the Trp residues in PPO, but had no effect on that around Tyr residues. Circular dichroism (CD) results showed that hesperetin increased α-helix content and decreased β-fold and random coil contents, thus tightening PPO's structure. Molecular docking showed that hesperetin entered the hydrophobic cavity of PPO, bound near the dinuclear copper active center, interacted with Val283, Phe264, His85, Asn260, Val248, and His263 via hydrophobic interactions, formed hydrogen bonds with Met280, His89, and His259 residues and also interacted with Phe292, His61, Phe90, Glu256, His244, Asn260, Phe264, and Gly281 via van der Waals forces. The molecular dynamics simulation results also demonstrated that the addition of hesperetin reduced the stability and hydrophobicity of PPO and increased PPO's structural denseness. Thus, the inhibition of hesperetin on PPO may be because hesperetin bound near the active center of PPO, interacted with the surrounding residues, occupied the binding site for substrate, and induced the changes in PPO's secondary structure, thus inhibiting the catalytic activity of PPO. This study may provide novel views for the inhibition of hesperetin on PPO and theoretical guidance for developing flavonoids as new and efficient PPO inhibitors.

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Inhibitory Mechanism of Baicalein on Acetylcholinesterase: Inhibitory Interaction, Conformational Change, and Computational Simulation.

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