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

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Authors:
D. Huang; U. Lüthi; P. Kolb; K. Edler; M. Cecchini; S. Audetat; A. Barberis; A. Caflisch

Journal: J. Med. Chem.
Year: 2005
Volume: 48
Issue: 16
Pages: 5108-5111
DOI: 10.1021/jm050499d
Type of Publication: Journal Article

Keywords:
Amyloid 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.