Discovery of cell-permeable non-peptide inhibitors of β-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. EC50 values less than 10 mu M 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.