title: Identification of a sub-micromolar, non-peptide inhibitor of β-secretase with low neural cytotoxicity through in silico screening.
abstract: Nowadays identification of novel non-peptide β-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 IC(50) values of 0.53 and 9.4 μM. 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.
authors: School of Chemical and Life Sciences, Singapore Polytechnic, Singapore.
authors: Weijun
authors: W
authors: Xu
authors: Gang
authors: G
authors: Chen
authors: Weiliang
authors: W
authors: Zhu
authors: Zhili
authors: Z
authors: Zuo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D011720:Pyrazoles; D053829:Amyloid Precursor Protein Secretases