Biological Implications of the Intrinsic Deformability of Human Acetylcholinesterase Induced by Diverse Compounds: A Computational Study

Abstract

The enzyme acetylcholinesterase (AChE) plays a crucial role in the termination of nerve impulses by hydrolyzing the neurotransmitter acetylcholine (ACh). The inhibition of AChE has emerged as a promising therapeutic approach for the management of neurological disorders such as Lewy body dementia and Alzheimer's disease. The potential of various compounds as AChE inhibitors was investigated. In this study, we evaluated the impact of natural compounds of interest on the intrinsic deformability of human AChE using computational biophysical analysis. Our approach incorporates classical dynamics, elastic networks (ENM and NMA), statistical potentials (CUPSAT and SWOTein), energy frustration (Frustratometer), and volumetric cavity analyses (MOLE and PockDrug). The results revealed that cyanidin induced significant changes in the flexibility and rigidity of AChE, especially in the distribution and volume of internal cavities, compared to model inhibitors such as TZ2PA6, and through a distinct biophysical-molecular mechanism from the other inhibitors considered. These findings suggest that cyanidin could offer potential mechanistic pathways for future research and applications in the development of new treatments for neurodegenerative diseases.

Keywords: AChE inhibitors; Alzheimer’s disease; structural flexibility.

Figure 1

Structures of (a) resveratrol (CID: 445154), (b) cyanidin (CID: 128861), (c) bis-(-)-8-demethylmaritidine (CID: 169450457), (d) huperzine A (CID: 854026), and (e) TZ2PA6 (CID: 5289508) drawn using ChemSketch Freeware.

Figure 1

Structures of (a) resveratrol (CID: 445154), (b) cyanidin (CID: 128861), (c) bis-(-)-8-demethylmaritidine (CID: 169450457), (d) huperzine A (CID: 854026), and (e) TZ2PA6 (CID: 5289508) drawn using ChemSketch Freeware.

Figure 2

Minimum energy structures of (a) TZ2PA6 and (b) cyanidin coupled to AChE after 500 ns MD simulations.

Figure 3

Root mean square deviation (RMSD) (a), root mean square fluctuation (RMSF) (b), radius of gyration (Rg) (c), and (d) depletion of hydrophobic, electrostatic, and hydrogen bonding interactions of minimum energy complexes AChE with and without ligands after 500 ns of MD simulations.

Figure 3

Root mean square deviation (RMSD) (a), root mean square fluctuation (RMSF) (b), radius of gyration (Rg) (c), and (d) depletion of hydrophobic, electrostatic, and hydrogen bonding interactions of minimum energy complexes AChE with and without ligands after 500 ns of MD simulations.

Figure 3

Root mean square deviation (RMSD) (a), root mean square fluctuation (RMSF) (b), radius of gyration (Rg) (c), and (d) depletion of hydrophobic, electrostatic, and hydrogen bonding interactions of minimum energy complexes AChE with and without ligands after 500 ns of MD simulations.

Figure 4

The top panel shows a graphical representation of the collective mobility of the nodes, indicated by a ribbon ranging from blue (low mobility) to red (high mobility), highlighting in a red circle parts of the complex (a) AChE (b) with TZ2PA6 and (c) with cyanidin after 500 ns of MD. The lower panel shows the same complexes, but this time it is represented by a ribbon ranging from blue (residues with a propensity to broadcast the response to a perturbation) to red (residues with a propensity to receive such perturbation) for the complexes (d) AChE, (e) with TZ2PA6, and (f) with cyanidin over the same period of time.

Figure 5

Graphical representation of the maximum values of minimally frustrated residues of the AChE protein system free and in the presence of each compound.

Figure 6

Boxplot of the distribution of the volumes of the internal cavities of the AChE protein system free and in the presence of each compound.

Figure 7

Tridimensional representation of internal cavities near the binding site. Only internal cavities with druggability probability = 1.0 are shown. In the red circle, an internal cavity near the binding pocket and the blue circles show other internal cavities in different regions with also a druggability probability = 1.0. (a) AChE (b) with TZ2PA6 and (c) with cyanidin after 500 ns of MD.