Identification of Novel BACE1 Inhibitors by Combination of Pharmacophore Modeling, Structure-Based Design and In Vitro Assay.

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.