In silico discovery of beta-secretase inhibitors

TitleIn silico discovery of beta-secretase inhibitors
Publication TypeJournal Article
Year of Publication2006
AuthorsHuang D., Lüthi U., Kolb P., Cecchini M., Barberis A., Caflisch A.
JournalJournal of the American Chemical Society
Date Published2006 Apr 26
Type of ArticleResearch Article
KeywordsAmyloid Precursor Protein Secretases, Electrochemistry, Models, Molecular, Protease Inhibitors

Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the β-amyloid precursor protein is initiated by β-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1. More than 300,000 small molecules were docked and about 15,000 prioritized according to a linear interaction energy model with evaluation of solvation by continuum electrostatics. Eighty-eight compounds were tested in vitro, and 10 of them showed an IC50 value lower than 100 μM in a BACE-1 enzymatic assay. Interestingly, the 10 active compounds shared a triazine scaffold. Moreover, four of them were active in an assay with mammalian cells (EC50 < 20 μM), indicating that they are cell-permeable. Therefore, these triazine derivatives are very promising lead candidates for BACE-1 inhibition. The discoveries of this series and two other series of nonpeptidic BACE-1 inhibitors demonstrate the usefulness of our in silico high-throughput screening approach.



Alternate JournalJ. Am. Chem. Soc.
PubMed ID16620115
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