Structural Dynamics and Susceptibility of Anti-Alzheimer’s Drugs Donepezil and Galantamine against Human Acetylcholinesterase

Abstract

Alzheimer’s disease (AD) is a major public health problem worldwide due to an increase in the elderly population. The current pharmacotherapy for the early stages of AD is mainly dependent on cholinesterase inhibitors. Two of the most commonly used anti-AD drugs, donepezil (DPZ) and galantamine (GLM), are selective inhibitors for human acetylcholinesterase (hAChE). However, the inhibitory activity of DPZ on hAChE was more potent than GLM by ~85 times. To better understand the molecular basis for differences in mode of inhibition of hAChE by both drugs, molecular dynamics (MD) simulation was performed. The results showed that the active site residues of hAChE/DPZ had the higher hydrogen bond occupancies as compared to hAChE/GLM. Nevertheless, the 2 drugs directly formed hydrogen bonds with the catalytic residue H447 of hAChE. The per-residue free energy decomposition suggested that DPZ interacted with the residues in peripheral anionic site of hAChE, resulting in the greater binding affinity of DPZ than that of GLM toward hAChE. The binding free energy calculation based on MM-PBSA and MM-GBSA methods indicated that van der Waal interactions played a predominant role as the driving force for binding process of DPZ and GLM to hAChE. Moreover, the predicted total binding free energy of hAChE/DPZ was stronger than hAChE/GLM, which was consistent well with the experimental data. We hope that our findings provide useful information for further design of novel hAChE inhibitors.
 HIGHLIGHTS
 
 Anti-Alzheimer’s drugs donepezil and galantamine in complex with human acetylcholinesterase were explored by MD simulations and binding free energy calculations
 The MM-PB(GB)SA-based binding free energy indicated that donepezil exhibited a more favorable binding affinity to human acetylcholinesterase than galantamine
 The molecular rotation of galantamine during MD simulation resulted in the reduction of hydrogen bond occupancies with D74 and S203
 The van der Waals interactions were considered as the major contributor to the binding of both drugs
 
 GRAPHICAL ABSTRACT