Pharmaceutical and Biomedical Research (Aug 2024)
Assessment of Potential Acetylcholinesterase Inhibitors: An In Silico Study
Abstract
Background: In the spectrum of neurodegenerative conditions, Alzheimer disease (AD) stands out as the predominant contributor to dementia and behavioral alterations. Cholinesterase inhibitors (ChE-Is) represent the primary pharmaceutical category currently endorsed for addressing AD. Objectives: This investigation assessed the potential of selected test compounds to inhibit cholinesterase, specifically targeting acetylcholinesterase (AChE), through in silico approaches. Methods: In this investigation, five test compounds—oxypertine, cinitapride, niaprazine, fenoverine, and clebopride—were identified and selected based on their electroshape resemblance to donepezil, utilizing the SwissSimilarity web server. Molecules with shapes similar to donepezil can fit into the AChE active site more snugly, facilitating similar interactions. AChE (PDB ID: 6U34) was sourced from the RCSB Protein Data Bank (PDB) and prepared for molecular docking with Discovery Studio 2020 software. Molecular docking was executed using PyRx, while visualization was performed with Discovery Studio 2020 software. Furthermore, the physicochemical properties (adhering to Lipinski’s rule of five), drug-likeness, and various parameters, encompassing absorption, distribution, metabolism, elimination, and toxicity (ADMET) profiles of the test compounds were scrutinized utilizing the SwissADME server. These findings were juxtaposed with those of donepezil, the standard drug. Results: The docking scores revealed that fenoverine (-10.40 kcal/mol) exhibits greater potency against 6U34 compared to donepezil (-10.30 kcal/mol), while clebopride, cinitapride, niaprazine, and oxypertine (-9.50, -9.40, -9.20, and -9.10 kcal/mol, respectively) demonstrated lower potency against 6U34 relative to donepezil. All compounds adhered to Lipinski’s drug-likeness rules and displayed promising ADMET profiles suitable for therapeutic applications as ChE-Is. Conclusion: Based on molecular docking and pharmacological parameters, fenoverine is a suitable alternative to donepezil. However, further studies using in vivo methods and other techniques are recommended to validate the results of this study.
