BACE1 Inhibition by Genistein: Biological Evaluation, Kinetic Analysis, and Molecular Docking Simulation.

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a role in generating amyloid β (Aβ), thus playing a major part early in the pathogenesis of Alzheimer's disease (AD). BACE1 has emerged as a crucial therapeutic target for decreasing the Aβ concentration in the AD brain. To explore natural BACE1 inhibitors, the present study concentrated on isoflavones, including genistein, formononetin, glycitein, daidzein, and puerarin. In this study, in vitro anti-AD activities were assessed using BACE1 inhibition assays, as well as enzyme kinetic predictions. Molecular docking analysis was applied to design potential BACE1 inhibitors. Among the major isoflavones, genistein exerted a notable BACE1 inhibition through reversible noncompetitive mechanism, while other compounds were less potent against BACE1. The docking study revealed that genistein had negative binding energy (-8.5 kcal/mol) and was stably positioned in the allosteric domains of BACE1 residues. It interacted with important amino acid residues in BACE1, such as ASN37, GLN73, and TRP76, through hydrogen bonding. The results suggested that genistein may be beneficial for preventing and/or treating AD. Furthermore, it may provide potential guidelines for the design of new BACE1 inhibitors.