Molecular docking and quantum mechanical studies on biflavonoid structures as BACE-1 inhibitors

Beta-site amyloid precursor protein cleaving enzyme (BACE-1) is a well-known therapeutic target for Alzheimer disease (AD) due to its characteristic role in the pathogenesis of AD. Numerous researches have been focused on the design and development of potent peptidic and non-peptidic BACE-1 inhibitors. In the present contribution, a series of experimentally validated biflavonoid BACE-1 inhibitors ( 1 – 21 ) were subjected to our structure-based molecular modeling studies. Binding modes were elucidated through molecular docking in the active site of the enzyme. Relatively good correlations between the theoretical and experimental binding affinities could be achieved ( R 2 = 0.61). Analysis of intermolecular binding energy components was performed via functional B3LYP in association with split-valence basis set using polarization functions (Def2-SVP), and structure-binding relationships were further elucidated through ligand–residue binding energies. Since little studies have been performed on the modeling and structure activity/binding relationships of biflavonoid structures as BACE-1 inhibitors, the results of this study may be useful in further extending the scope of biflavonoid structures as potential anti-Alzheimer scaffolds.