Identification of Natural Compounds of the Apple as Inhibitors against Cholinesterase for the Treatment of Alzheimer’s Disease: An In Silico Molecular Docking Simulation and ADMET Study

Abstract

Alzheimer’s disease (AD), the most common type of dementia in older people, causes neurological problems associated with memory and thinking. The key enzymes involved in Alzheimer’s disease pathways are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Because of this, there is a lot of interest in finding new AChE inhibitors. Among compounds that are not alkaloids, flavonoids have stood out as good candidates. The apple fruit, Malus domestica (Rosaceae), is second only to cranberries regarding total phenolic compound concentration. Computational tools and biological databases were used to investigate enzymes and natural compounds. Molecular docking techniques were used to analyze the interactions of natural compounds of the apple with enzymes involved in the central nervous system (CNS), acetylcholinesterase, and butyrylcholinesterase, followed by binding affinity calculations using the AutoDock tool. The molecular docking results revealed that CID: 107905 exhibited the best interactions with AChE, with a binding affinity of −12.2 kcal/mol, and CID: 163103561 showed the highest binding affinity with BuChE, i.e., −11.2 kcal/mol. Importantly, it was observed that amino acid residue Trp286 of AChE was involved in hydrogen bond formation, Van Der Walls interactions, and Pi–Sigma/Pi–Pi interactions in the studied complexes. Moreover, the results of the Molecular Dynamics Simulation (MDS) analysis indicated interaction stability. This study shows that CID: 12000657 could be used as an AChE inhibitor and CID: 135398658 as a BuChE inhibitor to treat Alzheimer’s disease and other neurological disorders.

African Natural Products for Multitarget-Based Treatment of Alzheimer’s Disease: An In Silico Study

“…The active site of BuChE consists of a catalytic triad, a choline binding pocket, and an acyl binding pocket, which are immersed in a 20 Å deep gorge [44,45]. Three important residues, Ser198, His438, and Glu325, make up the catalytic triad, Gln119, Val288, Leu286 and Ala328 form the acyl binding pocket [44][45][46]. The residues, Phe329 and Trp332 of BuChE help pull ligands toward the inner gorge [45].…”

“…Three important residues, Ser198, His438, and Glu325, make up the catalytic triad, Gln119, Val288, Leu286 and Ala328 form the acyl binding pocket [44][45][46]. The residues, Phe329 and Trp332 of BuChE help pull ligands toward the inner gorge [45]. BuChE also has Asp70 and Trp82 residues in the peripheral anionic pocket that also support ligand binding [45].…”

“…The residues, Phe329 and Trp332 of BuChE help pull ligands toward the inner gorge [45]. BuChE also has Asp70 and Trp82 residues in the peripheral anionic pocket that also support ligand binding [45].…”

“…The other two H-bonds were formed with a water molecule in the active site. Moreover, multiple important π-π stacking hydrophobic bonds were noticed between compound 27 aromatic system, with the aromatic amino acids His438 (which is part of the catalytic triad), Trp82 (found in the peripheral anionic pocket and supports ligand binding), and Phe329 (which help to attract the compound toward the deep gorge and the catalytic triad) [45]. Compound 147 (Figure 3c) formed T shaped π-π stacking hydrophobic with the aromatic amino acids Phe329 and Trp231 which are key residues and major acyl loop components that help in the interaction.…”

“…Compound 147 (Figure 3c) formed T shaped π-π stacking hydrophobic with the aromatic amino acids Phe329 and Trp231 which are key residues and major acyl loop components that help in the interaction. There are three H-bonds between three water molecules inside the active site and the carbonyl group of compound 147 [45]. The interaction of compound 157 (Figure .3d) involved mainly π-π stacking hydrophobic of its aromatic ring with His438 (one of the important aromatic catalytic triad amino acids).…”