Abstract
Acetylcholinesterase (AChE) is the key enzyme that breaks down and deactivates acetylcholine, thereby regulating the concentration of neurotransmitters at the synapses. Inhibition of AChE is considered a potential approach for treating Alzheimer’s disease. The plethora of natural products is undoubtedly a possible source of AChE inhibitors. Given the adverse side effects of currently marketed medications, we sought to investigate 94 compounds linked to their remarkable AChE inhibition properties along with their IC50 values procured from previous wet lab results. With a thorough in silico analysis that included molecular docking, molecular dynamics (MD) simulation, molecular mechanics Poisson-Boltzmann Surface Area (MM/PBSA), density functional theory (DFT) study, and pharmacokinetic properties, we identified the most potent compound for inhibition of AChE. Significant hydrogen bonding with the catalytic triad residues of AChE, prominent MM/PBSA binding energy of -28.97 KJ/mol, and the stable nature of protein-ligand complex about 100ns MD simulation screened macelignan as the best AChE inhibitor. Macelignan, with a binding affinity of -10.6 kcal/mol, demonstrated a greater binding interaction with AChE than the reference drug, rivastigmine. In addition, it exhibits significant reactivity in the substrate binding pocket of AChE and an inhibitory concentration (IC₅₀) of 4.16 土 0.070 µM. This outcome is further supported by favorable pharmacokinetic properties displaying the positive result towards Lipinski’s rule of Five, and negative result towards hepatotoxicity and AMES toxicity. This study carries a perspective for AChE inhibition and suggests macelignan as a potential therapy for Alzheimer’s disease; further research is necessary.