Uncovering the Binding Mode of γ -Secretase Inhibitors

Knowledge of how transition state inhibitors bind to γ-secretase is of major importance for the design of new Alzheimer’s disease therapies. On the basis of the known structure of γ-secretase in complex with a fragment of the amyloid precursor protein, we generated a structural model of γ-secretase in complex with the effective L-685,458 transition state inhibitor. The predicted binding mode is in excellent agreement with experimental data, mimicking all enzyme–substrate interactions at the active site and forming the relevant transition state geometry with the active site aspartate residues. The model also indicates the possible location and nature of the amino acid residues forming the proposed binding pockets S1′, S2′, and S3′ near the active site that are occupied by chemical groups of the inhibitor. In addition, we found that the stability of the complex is very likely sensitive to the pH value. Comparative simulations on the binding of L-685,458 and the epimer L682,679 allowed us to explain the strongly reduced affinity of the epimer for γ-secretase. The structural model could form a valuable basis for the design of new or modified γ-secretase inhibitors.