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.
Highlights
Alzheimer’s disease (AD), a progressive neurodegenerative disease featuring hidden onset, is clinically the most prevalent dementia form, which manifests as cognitive impairment, such as memory loss, out-of-control behaviour, and emotional disorder [1,2]
The present study investigated the inhibitory action of baicalein on AChE and the underlying mechanism at the molecular level by using several spectroscopic and computer simulation techniques
The hydrogen bond and hydrophobic interaction aided the binding between baicalein and AChE
Summary
Alzheimer’s disease (AD), a progressive neurodegenerative disease featuring hidden onset, is clinically the most prevalent dementia form, which manifests as cognitive impairment, such as memory loss, out-of-control behaviour, and emotional disorder [1,2]. According to Alzheimer’s Disease International’s data in September 2021, the number of AD patients worldwide is 55 million. The aetiology of AD is currently unknown [5]. Scholars both at home and abroad have proposed multiple hypotheses about its pathogenesis, among which the “cholinergic hypothesis” is the most developed and well-known [6,7,8]. Degeneration of basal cholinergic neurons in the forebrain and loss of associated cholinergic neurotransmitters in the cerebral cortex and other regions lead to the degradation of cognitive function in AD patients [9]. Acetylcholinesterase (AChE, Acetylcholinesterase, E.C.3.1.1.7) is a serine protease that catalyses the hydrolysis of acetylcholine (ACh), an essential neurotransmitter in vivo, and decomposes it into acetic acid and choline, blocking nerve impulse transmission [10,11]
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