Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations

TitleDiscovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations
Publication TypeJournal Article
Year of Publication2005
AuthorsHuang D., Lüthi U., Kolb P., Edler K., Cecchini M., Audetat S., Barberis A., Caflisch A.
JournalJournal of Medicinal Chemistry
Volume48
Issue16
Pagination5108-5111
Date Published2005 Aug 11
Type of ArticleResearch Article
ISSN0022-2623
KeywordsAmyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Binding Sites, Carbanilides, Cell Line, Cell Membrane Permeability, Databases, Factual, Endopeptidases, Fluorescence Resonance Energy Transfer, Mammals, Models, Molecular, Phenylurea Compounds, Static Electricity, Structure-Activity Relationship, Thiadiazoles
Abstract

A fragment-based docking procedure followed by substructure search were used to identify active-site β-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC50 values less than 10 μM were measured in at least one of two different mammalian cell-based assays for 12 of the 72 purchased compounds. In particular, the phenylureathiadiazole 2 and the diphenylurea derivative 3 are promising lead compounds for β-secretase inhibition.

DOI10.1021/jm050499d
pubindex

0067

Alternate JournalJ. Med. Chem.
PubMed ID16078830
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