Structure‐based Virtual Screening and Biological Characterization of Novel BACE‐1 and Amyloid‐β Aggregation Inhibitors

Alzheimer’s disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta‐site APP cleaving enzyme 1 (BACE‐1) is a key target for therapeutic intervention in Alzheimer’s disease. To discover new scaffolds for BACE‐1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure‐based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE‐1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35% inhibitory activity at 10 µM. Notably, pyrazole‐5‐carbohydrazide 29 (5784196) exhibited BACE‐1 inhibition with an IC50 value of 14.5 µM and a ki value of 0.25 μM. Additionally, it also inhibits the self‐aggregation of β‐amyloid, with IC50 value of 14.87 µM. Molecular modeling and dynamics simulations provided insights into its interaction pattern and stability of the enzyme‐inhibitor complex. These findings suggest that virtual screening is an efficient and cost‐effective method for identifying potential leads for AD.