Abstract b-Secretase is an important protease in the pathogenesis of Alzheimers disease. Some statine-based peptidomimetics
show inhibitory activities to the b-secretase. To explore the inhibitory mechanism, molecular docking and three-dimensional quantitative
structureĘCactivity 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 b-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 b-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 b-secretase. Therefore, the final 3D-QSAR models and the information of the
inhibitorĘCenzyme interaction would be useful in developing new drug leads against Alzheimers disease.