Molecular docking and structure-activity relationship studies on benzothiazole based non-peptidic BACE-1 inhibitors.
A similarity search on the structural analogs of an inhibitor of BACE-1 with IC(50) 2.8μM, which contained a P1 benzothiazole group together with a triazine ring linked by a secondary amine group, was described in this Letter and some more potent inhibitors against BACE-1 were identified. The most potent compound 5 (IC(50)=0.12μM) increases the inhibitory potency by 24 folds. Our results suggest that a pyrrolidinyl side group at the P3' and P4' of the inhibitors are favored for strong inhibition and a small aromatic group at the P4 position is also essential to the potency.
Xu
Weijun
W
School of Chemical and Life Sciences, Singapore Polytechnic, Singapore 139651, Singapore.
Chen
Gang
G
Zhu
Weiliang
W
Zuo
Zhili
Z
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human