Novel non-peptide beta-secretase inhibitors derived from structure-based virtual screening and bioassay.
This Letter describes an efficient approach by integrating virtual screening with bioassay technology for finding small organic inhibitors targeting beta-secretase (BACE-1). Fifteen hits with inhibitory potencies ranging from 2.8 to 118 microM (IC(50)) against beta-secretase were successfully identified. Compound 12 with IC(50) of 2.8 microM is the most potent hit against BACE-1. Docking simulation from gold 3.0 suggests putative binding mode of 12 in BACE-1 and potential key pharmacophore groups for further designing of non-peptide compounds as more powerful inhibitors against BACE-1.
Xu
Weijun
W
School of Chemical and Life Sciences, Singapore Polytechnic, Singapore 139651.
Chen
Gang
G
Liew
Oi Wah
OW
Zuo
Zhili
Z
Jiang
Hualiang
H
Zhu
Weiliang
W
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D020128:Inhibitory Concentration 50; D009930:Organic Chemicals / Q000494:pharmacology; D011485:Protein Binding
D009930:Organic Chemicals; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human