Study on the active mechanism of β-secretase inhibitors by molecular simulations

Graphical abstractThe proteolytic enzyme β-secretase (BACE-1) is one of potential drug targets for treating Alzheimers’s disease. The reliable and accurate models of 3D QSAR, molecular docking and molecular dynamic simulations for the BACE-1 and its inhibitors were established, and the several important structural factors that mainly influence the inhibitory activity were obtained. Furthermore, several new derivatives were designed. Our studies expounded the binding mechanism between BACE-1 and its inhibitors, which provide some insights into the further structural modification and the development of new potent inhibitors with higher activity.Figure optionsDownload full-size imageDownload high-quality image (114 K)Download as PowerPoint slide

The proteolytic enzyme β-secretase (BACE-1) is one of potential drug targets for treating Alzheimers’s disease. First, the reliable and accurate models of three-dimensional quantitative structure-activity relationship for the BACE-1 inhibitors were established, and the several important structural factors that mainly influence the inhibitory activity were obtained. Second, the results of molecular docking presented the binding mode between BACE-1 and its inhibitors, and molecular dynamic simulations provided the details of the receptor–ligand interactions. Furthermore, several new derivatives were designed and validated based on these theoretical analyses. Our studies revealed the binding mechanism between BACE-1 and its inhibitors, and provide some insights into the further structural modification and the design of new inhibitors with higher activity.