Exploration of Acetylcholinesterase Inhibitors Based on Molecular Modeling, Molecular Docking, and Molecular Dynamics Simulations

ABSTRACT Alzheimer's disease (AD) is a neurodegenerative brain disease that affects tens of millions of people worldwide, and it is characterized by memory impairment and cognitive deficits. Acetylcholinesterase (AChE) inhibitors can improve cognitive ability and memory, and are currently the focus of research to treat AD. In this paper, 41 donepezil analogues are studied by QSAR models, the reliable HQSAR ( q 2 = 0.825, r 2 = 0.962, N = 6, and SEE = 0.167) and Topomer CoMFA models ( q 2 = 0.843, r 2 = 0.994, N = 6, and SEE = 0.098) are obtained. Both external validation and application domain also indicate the reliability of the models. Based on these two models, 33 new compounds are successfully designed through virtual screening; they have good theoretical inhibitory activity. The molecular docking results show that these compounds bind tightly to proteins. ADMET predictions also confirm that most of these compounds meet the medicinal requirements. Molecular dynamics (MD) simulations are performed for four new compounds, and the results further verify the reliability and stability of the new compounds. This study provides a theoretical guide for the use of AChE inhibitor to treat AD, and the new compounds designed are expected to be novel drugs for AD.