In silico screening of naturally derived dietary compounds as potential butyrylcholinesterase inhibitors for Alzheimer's disease treatment

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes a substantial decline in cognitive functions and affects memory, thinking abilities, and daily behavior. The most prominent hallmark of AD pathogenesis is the formation of amyloid-β plaques, among other associated pathways such as neurofibrillary tangles, mitochondrial dysfunction, neuroinflammation, and oxidative stress. Butyrylcholinesterase (BuChE), an acetylcholine-degrading enzyme, plays a critical role in the progression of Alzheimer's disease, particularly through its involvement in amyloid-β plaque formation. Thus, the inhibition of BuChE is considered a valuable therapeutic strategy for the management of AD. The present study aimed to identify potential bioactive chemicals from naturally occurring dietary compounds that could improve neurocognitive function and appear as a viable treatment for AD by inhibiting the function of BuChE. A small library of 44 natural dietary chemicals from a variety of dietary plants was subjected to comprehensive in silico studies, including molecular docking, molecular mechanics generalized born surface area (MM-GBSA) calculations, pharmacokinetics assessments, toxicity profiles, molecular dynamics (MD) simulation, and density functional theory (DFT) analysis. These studies revealed that CID 129886986 and CID 115269 showed stronger binding affinities with drug-likeness and no toxicity than the FDA-approved standard drug, Donepezil. Additionally, they exhibited strong structural stability with fewer fluctuations throughout the simulation, making them promising candidates for Alzheimer's disease treatment.

Keywords: Alzheimer’s disease; Butyrylcholinesterase; Density functional theory; MM-GBSA; Molecular docking; Molecular dynamics simulations; Pharmacokinetics.

Fig. 1

The 3D X-ray crystal structure of human butyryl cholinesterase protein (PDB ID: 1P0I).

Fig. 2

Molecular docking configurations and interactions with 1P0I protein. The complexes of protein–ligand interactions in 2D are presented on the right side, while the 3D observations are shown on the left. (A) CID 3152; (B) CID 115269; (C) CID 445154; and (D) CID 129886986.

Fig. 3

Illustrating the MM-GBSA analysis results for compounds CID 445154, CID 115269, and CID 129886986, and the control compound CID 3152, examining their binding interactions with the target receptor 1P0I.

Fig. 4

RMSD values of the docked protein–ligand complexes over a 250-ns simulation time. The colors orange, blue, and purple, respectively, represented docked protein with the three compounds CID 3152, CID 115269, and CID 129886986, while green represented apo-protein.

Fig. 5

RMSD values of the docked ligands over 250 simulation run time. The colors orange, blue, and purple were used to represent the compounds CID 3152, CID 115269, and CID 129886986, respectively.

Fig. 6

RMSF analysis of the residues of amino acids during a 250 ns simulation period. The protein Cα atoms in the protein–ligand complexes were used to calculate the RMSF values. Green represents Apo-protein 1P0I, whereas orange, blue, and purple represent the three complexes bound to CID 3152, CID 115269, and CID 129886986, respectively.

Fig. 7

Rg values of the protein–ligand complexes across a 250 ns simulation timeline. The colors orange, blue, and purple, respectively, represent the complexes of the three compounds CID 3152, CID 115269, and CID 129886986 with 1P0I.

Fig. 8

SASA values of the ligand–protein complexes over the course of the 250 ns simulation. The colors for the protein complexed with CID 3152, CID 115269, and CID 129886986 were orange, blue, and purple, according to this order.

Fig. 9

Graphical representation of the PCA analysis of (A) apo (1P0I) protein, (B) CID 3152-1P0I complex, (C) CID 115269-1P0I complex, (D) CID 129886986-1P0I complex, where red and blue dots show the simulation’s illustration of protein conformational changes.

Fig. 10

Cα-residue cross-correlation profiles for (A) apo (1P0I) protein, (B) CID 3152-1P0I complex, (C) CID 115269-1P0I complex, (D) CID 129886986-1P0I complex.

Fig. 11

Free energy landscape (FEL) Analysis for (A) apo (1P0I) protein, (B) CID 3152-1P0I complex, (C) CID 115269-1P0I complex, (D) CID 129886986-1P0I complex. The energy increases in the order of violet < blue < green < yellow < red < dark red.

Fig. 12

The HOMO and LUMO molecular orbitals of the selected candidate drug molecules CID 115269, CID 129886986, and standard drug molecule CID 3152.