Robust and predictive 3D-QSAR models for predicting the activities of novel oxadiazole derivatives as multifunctional anti-Alzheimer agents

Abstract

In recent years, Alzheimer disease (AD) as a neurodegenerative disorder has been increasing annually with the aging of the global population, therefore, development of novel anti-AD drugs is imperative. Studies have proven that glycogen synthase kinase-3β (GSK-3β) is a pivotal factor in the development of AD. Therefore, GSK-3β inhibitors would provide powerful means to treat the disorders, such as AD. To in-depth study the structure–activity relationship of a series of oxadiazole derivatives as multifunctional anti-Alzheimer agents, computational three dimensional quantitative structure–activity relationship (3D-QSAR) studies, molecular docking and molecular dynamics were conducted. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were conducted to build up the 3D-QSAR models, and exhibited significant results (R_cv² = 0.692, R_pred² = 0.6885/CoMFA, R_cv² = 0.696, R_pred² = 0.6887/CoMSIA). The accuracy of the 3D-QSAR models was validated by external validation and applicability domain analysis. The derived contour maps provided structural information for designing novel compounds to improve the inhibitory activities. Additionally, molecular docking and molecular dynamics were also employed to investigate the bonding interactions and stability of this series of inhibitors in the active site of GSK-3β, and the results revealed that the importance of residues Ile62, Asn64 Val70, Tyr128, Val129 and Leu182 for ligand binding to the receptor GSK-3β. All the results would be of great help for the discovery of new GSK-3β agents that can solve the problem of AD.