High-throughput virtual screening approach and dynamic simulation of natural compounds as target inhibitors of BACE1 in Alzheimer's disease

Abstract

Background Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein holds significance in the development of Alzheimer’s disease (AD). This protein is highly expressed in the central nervous system, playing a significant role in the conversion of amyloid precursor protein (APP) into amyloid-beta peptides. The primary objective of the current study was to perform in silico inhibition investigations on this protein, utilizing computational methodologies such as molecular docking and molecular dynamics, to identify novel inhibitors with potential against BACE1. Our focus was on targeting the active site of BACE1, aiming to discover optimal interactions between the ligands and key residues of the target protein. Methods The natural compounds inhibitors data was carefully reviewed from the literature review articles. Molecular docking was conducted using AutoDock Vina with an active site defined by CB-Dock2. We assessed drug-likeness and toxicity using Lipinski’s rule of fives via SwissADME and the ProTox-II web server. Interaction visualization was facilitated using Discovery Studio, while molecular dynamics simulations were performed for 100 nanoseconds with hinokiflavone and BACE1 using Schrodinger LLC Desmond software. Results The molecular docking results showed promising binding affinities and the best binding free energy values were selected, and after conducting Lipinski’s rule of five using SwissADME as well as predicting toxicity using ProTox-II, only one molecule, hinokiflavone was filtered and succeeded in all the analyses to be a potential candidate. Molecular docking results were supported by molecular dynamics simulation. These results demonstrate the stability of the compound in the target protein binding site. Conclusions Finally, these obtained outcomes represent a strong lead to developing promising new natural compound inhibitors against BACE1. For future works, it is essential to concentrate on further experimental validation to ensure the effectiveness of the proposed approach.