Uncovering the Binding Mode of γ-Secretase Inhibitors

Knowledge of how transition state inhibitors bind to{gamma} -secretase is of major importance for the design of new Alzheimers disease therapies. Based on the known structure of{gamma} -secretase in complex with a fragment of the amyloid precursor protein we have generated a structural model of{gamma} -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. In addition, we found that the stability of the complex is very likely also 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{gamma} -secretase. The structural model could form a valuable basis for the design of new or modified{gamma} -secretase inhibitors.