Identification of a sub-micromolar, non-peptide inhibitor of b-secretase with low neural cytotoxicity through in silico screening

Weijun Xu, Gang Chen, Hualiang Jiang, Weiliang Zhu, Zhili Zuo

Nowadays identification of novel non-peptide b-secretase (BACE-1, hereinafter) inhibitors with low cytotoxicity
and good blood–brain barrier (BBB) property holds common interest of drug discovery for
Alzheimer's disease. Twenty SPECS compounds were tested in BACE-1 FRET assays and methylthiazoletetrazolium
(MTT) cytotoxicity experiment. Two compounds: 2 and 15 demonstrated IC50 values of
0.53 and 9.4 lM. In addition, 2 showed least toxic effect to the neuroblastoma cells. The results from both
in silico and in vitro studies provided new pharmacophoric entities for chemical synthesis and optimization
on the current discovered BACE-1 small molecule inhibitors.