Uncovering the Binding Mode of γ-Secretase Inhibitors

Manuel Hitzenberger, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish
Pages (from-to)3398-3403
Number of pages6
JournalACS Chemical Neuroscience
Issue number8
StatePublished - 21 Aug 2019
Externally publishedYes


  • enzyme dynamics
  • enzyme inhibition
  • ligand-receptor docking
  • γ-Secretase drug binding
  • γ-secretase transition state inhibition


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