Molecular docking and 3D-QSAR studies on the binding mechanism of statine-based peptidomimetics with β-secretase Original Research Article

β-Secretase is an important protease in the pathogenesis of Alzheimer’s disease. Some statine-based peptidomimetics show inhibitory activities to the β-secretase. To explore the inhibitory mechanism, molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies on these analogues were performed. The Lamarckian Genetic Algorithm (LGA) was applied to locate the binding orientations and conformations of the peptidomimetics with the β-secretase. A good correlation between the calculated binding free energies and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, highly predictive 3D-QSAR models were developed with q2 values of 0.582 and 0.622 for CoMFA and CoMSIA, respectively. The predictive abilities of these models were validated by some compounds that were not included in the training set. Furthermore, the 3D-QSAR models were mapped back to the binding site of the β-secretase, to get a better understanding of vital interactions between the statine-based peptidomimetics and the protease. Both the CoMFA and the CoMSIA field distributions are in well agreement with the structural characteristics of the binding groove of the β-secretase. Therefore, the final 3D-QSAR models and the information of the inhibitor–enzyme interaction would be useful in developing new drug leads against Alzheimer’s disease.