Abstract
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) mediate the degradation of acetylcholine (ACh), a primary neurotransmitter in the brain. Cholinergic deficiency occurs during the progression of Alzheimer’s disease (AD), resulting in widespread cognitive dysfunction and decline. We evaluated the potential effect of a natural cholinesterase inhibitor, zerumbone, using in vitro target enzyme assays, as well as in silico docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) simulation. Zerumbone showed a predominant cholinesterase inhibitory property with IC50 values of 2.74 ± 0.48 µM and 4.12 ± 0.42 µM for AChE and BChE, respectively; however, the modes of inhibition were different. Computational docking simulation indicated that Van der Waals interactions between zerumbone and both the cholinesterases were the main forces responsible for its inhibitory effects. Furthermore, zerumbone showed the best physicochemical properties for both bioavailability and blood–brain barrier (BBB) permeability. Together, in the present study, zerumbone was clearly identified as a unique dual AChE and BChE inhibitor with high permeability across the BBB, suggesting a strong potential for its physiological benefits and/or pharmacological efficacy in the prevention of AD.
Highlights
Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by an irreversible degeneration of neurons, leading to the impairment of cognitive functions
All data were represented as the mean ± standard deviation (SD) in three independent experiments, each performed in triplicates
The novel finding in our study was that zerumbone plays as a unique dual AChE and BChE inhibitor with strong
Summary
Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by an irreversible degeneration of neurons, leading to the impairment of cognitive functions. Toxicity, as well as low bioavailability form the major factors that restrict the in vivo efficacy of anti-AD agents at the target sites. Prior evaluation of the physicochemical characteristics of candidate compounds, as well as the analysis of their pharmacokinetic and toxicity properties, is a crucial prerequisite for the screening and selection of potential anti-AD agents. The compound has been found to exert a broad range of potential biological effects, such as hepatoprotective, antioxidant, immunoregulatory, anti-inflammatory, and anticancer activities [7,8,9,10]. Despite numerous studies on zerumbone, its direct effect on cognitive functions and dementia has not yet been elucidated. The present study focused on evaluating the inhibitory effect of zerumbone on AChE and BChE activities. The ability of zerumbone to reach the target site and interact with the targeted enzymes was investigated using in silico docking and ADMET simulation tools
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