Abstract
Excess Aβ production by the key protease BACE1, results in Aβ aggregation, forming amyloid plaques, all of which contribute to the pathogenesis of Alzheimer's disease. Besides the multi-factorial nature of the disease, the diversity in the size and shape of known ligands that bind to the active site of BACE1, that is the flexibility of the enzyme, pose a serious challenge for the identification of drug candidates. To address the issue of receptor flexibility we have carried out ensemble docking with multiple receptor conformations. Therein, two representative structures each from closed and semi-open BACE1 conformations were selected for virtual screening to identify compounds that bind to the active site of both the conformations. These outperformed compounds were ranked using pharmacophore models generated by a ligand-based approach, for the identification of BACE1 inhibitors. The inhibitors were further predicted for anti-amyloidogenic activity using a QSAR model already established by our group thus enlisting compounds with dual potency. BACE1 inhibitory and anti-amyloidogenic activity for the commercially available compounds were validated using in vitro studies. Thus, incorporation of receptor flexibility in BACE1 through ensemble docking in conjunction with structure and ligand-based approach for screening might act as an effective protocol for obtaining promising scaffolds against AD.