Jiancheng Shi, Wentong Tu and Chusheng Huang
College of Chemistry and Material Sciences, Guangxi Teachers Education University, China
To find promising new multitargeted Alzheimer's disease (AD) inhibitors, the three-dimensional quantitative structure-activity relationships (3D-QSAR) models for 32 AD inhibitors were established by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) methods. Results showed that the CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient (q2) and a non-cross-validated coefficient (R2), and the binding modes obtained by molecular docking were in agreement with the 3D-QSAR results, which suggests that the present 3D-QSAR model has good predictive capability to guide the design and structural modification of novel multitargeted AD inhibitors. Meanwhile, we found that one side of inhibitory molecule should be small group so that it would be conductive to enter the gorge to interact with the catalytic active sites of AChE, and the other side of inhibitory molecule should be large group so that it would be favorable for interaction with the peripheral anionic site of AChE. Furthermore, based on the 3D-QSAR models and the binding modes of AChE and BACE-1, the designed multitargeted AD molecules could act as dual binding inhibitors on AChE (act at catalytic and peripheral sites) and dual targets inhibitors (act at AChE and BACE-1). We hope that our results could provide hints for the design of new multitargeted AD derivatives with more potency and selective activity.