Beta-secretase (BACE1) inhibitor as a therapeutic approach for Alzheimer's disease through computational chemistry-based approaches

Recent theories for the cause of Alzheimer's disease (AD) include the deposition of amyloid peptide (Aβ) resulting from the breakdown of the Aβ precursor protein (APP) by beta-secretase (BACE-1), after which BACE-1 then also breaks down itself. Because BACE-1 regulates the production of Aβ protein, it represents a logical target for the development of therapeutics to inhibit the production of Aβ. Recent research measuring BACE-1 in normal and diseased human brains revealed that BACE-1 is a new class of type I membrane aspartic proteases. Targeting the protein associated with AD (e.g., tau pathology and cholinergic deficits) can modify the course of AD and improve cognitive function. Therefore, the pharmaceutical therapies currently available for treating AD have not been very effective, and clinical outcomes with existing medications are very poor due to the lack of any effective therapy available to prevent the eventual development of AD. Using molecular docking and molecular dynamics simulations we have been able to create new inhibitors. The PK and drug similarity profile of each molecule that was examined was also assessed using Lipinski's rule and ADMET analysis, respectively. The compound Arctigenin, when compared to the control compound Lanabecestat, and compounds from the compounds evaluated in this analysis, demonstrated the greatest predicted binding affinity to the BACE1 protein in the molecular docking study as well as less molecular dynamics variability. Individual RMSD, RMSF, Rg, SASA and H-bond results of all systems looked stable upon molecular dynamics simulation. The results of the PCA and FEL analysis of Arctigenin with BACE1 provided impressive results and indicate that further research studies will be necessary to evaluate the pharmacological similarity and PK profile of Arctigenin, and its potential as a therapeutic agent for AD via in vivo and in vitro models.