Computational Study of Natural Compounds for the Clearance of Amyloid-Βeta: A Potential Therapeutic Management Strategy for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (Aβ) peptides in senile plaques. The interaction of Aβ and the receptor for advanced glycation end products at the blood-brain barrier is also observed in AD, which not only causes the neurovascular anxiety and articulation of proinflammatory cytokines, but also directs reduction of cerebral bloodstream by upgrading the emission of endothelin-1 to induce vasoconstriction. In this process, RAGE is deemed responsible for the influx of Aβ into the brain through BBB. In the current study, we predicted the interaction potential of the natural compounds vincamine, ajmalicine and emetine with the Aβ peptide concerned in the treatment of AD against the standard control, curcumin, to validate the Aβ peptide-compounds results. Protein-protein interaction studies have also been carried out to see their potential to inhibit the binding process of Aβ and RAGE. Moreover, the current study verifies that ligands are more capable inhibitors of a selected target compared to positive control with reference to ΔG values. The inhibition of Aβ and its interaction with RAGE may be valuable in proposing the next round of lead compounds for effective Alzheimer's disease treatment.

Keywords: Alzheimer’s disease; Z-dock; binding energy; docking; natural compounds.

Figure 1

(A) The complex shows interacting amino acid residues and hydrogen bonds formed between compound ajmalicine (the ligand, ajmalicine, has been shown in green ‘stick’ representation) and β-Amyloid (B) The complex interacting amino acid residues and hydrogen bonds formed between compound emetine (the ligand, emetine, has been shown in green ‘stick’ representation) and β-Amyloid (C) The complex interacting amino acid residues and hydrogen bonds formed between compound vincamine (the ligand, vincamine, has been shown in green ‘stick’ representation) and β-Amyloid. (D) The complex interacting amino acid residues and hydrogen bonds formed between compound curcumin (the ligand, curcumin, has been shown in green ‘stick’ representation) and β-Amyloid.

Figure 2

Protein-protein interaction. (A) Aβ, (B) RAGE, (C) the complex of Aβ and RAGE obtained by the protein-protein docking method. Purple and brown stick color representations are the amino acid residues of Aβ and RAGE, respectively, involved in H-bond formation.

Figure 3

The complex-protein interaction. (A) The complex of Aβ+Ajm, (B) the complex of Aβ+Eme, (C) the complex of Aβ+Vnc. (D) Structure of RAGE protein. (E) The interacting complex structure of (Aβ+Ajm) with RAGE obtained by the protein-protein docking method. (F) The interacting complex structure of (Aβ+Eme) with RAGE obtained by the protein-protein docking method. (G) The interacting complex structure of (Aβ+Vnc) with RAGE obtained by the protein-protein docking method.

Figure 4

The three dimensional structures of the protein. (A) β-Amyloid (PDB ID: 2BEG). (B) Receptor for advanced glycation end products (RAGE) (PDB ID: 2ENS).

Figure 5

2D chemical structure of the compounds: (A) ajmalicine, (B) emetine, (C) vincamine, (D) curcumin.