P. Liu

The Discovery of Novel β‐Secretase Inhibitors: Pharmacophore Modeling, Virtual Screening, and Docking Studies

This article describes the identification of two small molecular inhibitors for β‐secretase by integrating virtual screening with fluorescence resonance energy transfer bioassay. A ligand‐based pharmacophore model was developed, and the sequential virtual screening of ZINC database was performed using the acquired pharmacophore model and molecular docking. Biological evaluation of 10 virtual hits led to the identification of two novel inhibitors with IC50 values of 4.76 and 0.31 μm, respectively. These two moderate inhibitors could represent new potentials for the development of anti‐Alzheimer’s disease agents.

Synthesis, in vitro Biological Evaluation and Molecular Docking Studies of Benzimidamides as Potential BACE1 Inhibitors

A series of 3, 5‐disubstituted benzimidamides were synthesized and biologically evaluated as potential BACE1 inhibitors. Both the targeted compounds (benzimidamides) and the synthetic intermediates (benzonitriles) were tested for their BACE1 inhibitory activities in a cell‐free FRET assay. All the synthesized benzimidamides were active as BACE1 inhibitors and compound 6d showed the lowest IC50 value of 3.35 μm. Molecular docking study proposed a binding mode, which would help to the further optimization on 6d to achieve more potent, BBB penetrant BACE1 inhibitors.