Modeling the binding affinities of β-secretase inhibitors: application to subsite specificity

A new linear binding affinity model has been developed for hydroxyethylene based inhibitors of β-secretase (BACE). This model is an improvement over a previously published model, and has been applied to a series of analogs not included in the training set. The linear model has been used to study subsite specificity for the P2 through positions, and to evaluate a small number of C-terminal analogs. The predicted rankings are in good agreement with experiment and support using this model for structure-based design of BACE inhibitors.