The protease β-secretase plays a critical role in the synthesis of pathogenic amyloid-β in Alzheimer’s disease.
In this study, pharmacophore constructed from receptor-ligand complex was used to screen Chemdiv and Zinc database
and the resulting hits were subjected to docking experiments using LiandFit and CDOCKER programs. Molecules with
high consensus scores and good interaction patterns in docking programs were retained. Drug-likeness assay including
Lipinski’s rule of five and ADMET properties filters were further used to identify BACE1 inhibitor. Finally, 13
compounds with novel scaffolds were selected and, considering of the nature of relative high LogP value of many
marketed AD drugs, three of them with top 3 predicted LogP value were evaluated for their IC50 values in vitro by
BACE1 enzymatic activity study. We believe that compound 13 with an IC50 value of 136 µM can be a lead compound
with great potential in BACE1 inhibition and increasing activity by subsequently structure modification or optimization.
At the same time, we found that the interaction between the residues Asp228, Asp32 of BACE1 and ligands is significant
through analyzing the binding mode of 13 candidate compounds.