BACE1 Inhibition Utilizing Organic Compounds Holds Promise as a Potential Treatment for Alzheimer's and Parkinson's Diseases

Abstract

Background: Neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) manifest through gradually deteriorating cognitive functions. An encouraging strategy for addressing these disorders involves the inhibition of precursor-cleaving enzyme 1 (BACE1).

Objectives: In the current research, a virtual screening technique was employed to identify potential BACE1 inhibitors among selected herbal isolates.

Methods: This study evaluated 79 flavonoids, anthraquinones (AQs), and cinnamic acid derivatives for their potential blood-brain barrier (BBB) permeability. Using the AutoDock 4.0 tool, molecular docking analysis was conducted to determine the binding affinity of BBB permeable compounds to the BACE1 active site. Molecular dynamics (MD) simulations were performed to assess the stability of the docked poses of the most potent inhibitors. The interactions between the most effective plant-based inhibitors and the residues within the BACE1 catalytic site were examined before and after MD simulations.

Results: Ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine were among the highest-ranking BACE1 inhibitors, with inhibition constant values calculated in the nanomolar range. Furthermore, during 10 ns simulations, the docked poses of these ligands were observed to be stable.

Conclusion: The findings propose that ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine might serve as potential choices for the treatment of AD and PD, laying the groundwork for the creation of innovative BACE1 inhibitors.

Figure 1

By plotting the compounds' ID on the x-axis and their estimated binding energies (kcal/mol) on the Y-axis, the study presented the ΔG_binding values between the most potent herbal inhibitors, positive control compounds, and the BACE1 active site. The blue diamonds represented control compounds, while the yellow spots depicted the top-ranked inhibitors in the study. BACE1, β-site amyloid precursor protein cleaving enzyme 1.

Figure 2

Interaction types among residues within the BACE1 active site and (a) ponciretin, (b) danthron, (c) chrysophanol, (d) N-p-coumaroyltyramine, and (e) DB07206. Left and right images present interactions before and after MD simulations, respectively. BACE1, β-site amyloid precursor protein cleaving enzyme 1; DB07206, 6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE; MD, molecular dynamics.

Figure 3

(a) RMSD, (b) RMSF, (c) total energy, and (d) radius of gyration plots of BACE1 backbone atoms in the presence of top-ranked anthraquinones and DB07206 during a 100 ns MD simulation. The x-axis presents the residue in the plot (b) and the simulation time in other plots. The y-axis presents RMSD, RMSF, total energy, and radius of gyration in plots (a–d), respectively. The location of the asterisks in part (b) is within the protein's active site. RMSD, root-mean-square deviations; RMSF, root-mean-square fluctuation; BACE1, β-site amyloid precursor protein cleaving enzyme 1; MD, molecular dynamics; DB07206, 6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE.

Figure 4

The structures of BACE1 in the presence of (a) ponciretin, (b) chrysophanol, (c) danthron, (d) N-p-coumaroyltyramine, and (e) DB07206 were superimposed after a 100 ns MD simulation. The protein chains before and after the MD analysis are depicted in gray and blue, respectively. The anthraquinones are displayed in yellow and pink before and after the MD simulations. BACE1, β-site amyloid precursor protein cleaving enzyme 1; MD, molecular dynamics.