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Updated: Jun 5, 2025
A11-positive β-amyloid Oligomer Preparation and Assessment Using Dot Blotting Analysis
Published on: May 22, 2018
Structure-Based Virtual Screening and Biological Characterization of Novel BACE-1 and Amyloid-β Aggregation
Ankita Sharma1,2, Madhusmita Nayak3, Shikha Thakur4
1Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
Abstract:
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.
