Potential of Pueraria tuberosa (Willd.) DC. to rescue cognitive decline associated with BACE1 protein of Alzheimer's disease on Drosophila model: An integrated molecular modeling and in vivo approach.

The indispensable role of Beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) in Amyloid beta (Aβ) plaques generation and Aβ-mediated synaptic dysfunctions makes it a crucial target for therapeutic intervention in Alzheimer's disease (AD). In order to find out the potential inhibitors of BACE1, the present study focused on five phytochemicals from Pueraria tuberosa, namely, daidzin, genistin, mangiferin, puerarin, and tuberosin. A molecular docking study showed that all five phytochemicals presented the strongest BACE1 inhibition. Integrated molecular dynamics simulations and free energy calculations demonstrated that all five natural compounds have stable and favorable energies causing strong binding with the pocket site of BACE1 on 50 ns. All these molecules also passed Lipinski's rule of five. To validate the molecular modeling based findings, we primarily targeted the cognitive decline associated with BACE1 expression in AD flies with P. tuberosa. Significant improvement in cognitive decline was observed in AD flies in different behavioral assays such as Larval crawling assay (16.38%), Larval light preference assay (26.39%), Climbing assay (32.97%), Cold sensitivity assay (43.6%), and Thermal sensitivity assay (44.42%). The present findings suggest that P. tuberosa may be considered as a promising dietary supplement that can significantly ameliorate cognitive decline caused by BACE1 in Alzheimer's disease (AD).