Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations.
A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM 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 beta-secretase inhibition.
Huang
Danzhi
D
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Lüthi
Urs
U
Kolb
Peter
P
Edler
Karin
K
Cecchini
Marco
M
Audetat
Stephan
S
Barberis
Alcide
A
Caflisch
Amedeo
A
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D002224:Carbanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability; D016208:Databases, Factual; D010450:Endopeptidases; D031541:Fluorescence Resonance Energy Transfer; D008322:Mammals; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002224:Carbanilides; D010671:Phenylurea Compounds; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases