Computer-aided discovery of dual-target compounds for Alzheimer's from ayurvedic medicinal plants

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, driven by the accumulation of amyloid-beta plaques and neurofibrillary tangles. It involves the dysfunction of key enzymes such as Acetylcholinesterase (AChE) and β-secretase (BACE1), making them critical targets for therapeutic intervention. In this study we investigated an in-house library of 820 secondary metabolites obtained from Ayurvedic plants against AChE and BACE1 with the aim to discover novel leads for AD. Virtual screening resulted in 15 ligands, mostly belonging to the ursane-type or dammarene-type triterpene saponins of Centella asiatica, reestablishing the potency of this plant in drug discovery against AD. The binding affinities were further verified by molecular dynamics (MD) simulation trajectories, including root mean square fluctuations (RMSF), root mean square deviation (RMSD), hydrogen bonding analysis, Coulomb interaction calculation, Lennard-Jones interactions, and the total interaction energy. Moreover, extensive Principal Component Analysis (PCA) and Gibbs free energy landscape were performed. Our results demonstrated three compounds, namely (S)-eriodictyol 7-O-(6-β-O-trans-p-coumaroyl)-β-d-glucopyranoside, sitoindoside-X and 1,5-di-o-caffeoyl quinic acid as more effective in treating AD due to their comparable drug-like properties. Drug-likeness, structural chemistry, pharmacophore, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis support their potential for future drug development. To establish the effectiveness of these lead compounds against AD, additional experimental testing should be performed.

Fig 1. Diagram illustrating the effects of acetylcholinesterase (AChE) and β-secretase (BACE1) on signaling pathways, reducing the progression of Alzheimer’s disease.

Fig 2. Structure of (A) human acetylcholinesterase (AChE, PDB ID: 6O4W) and (B) β-secretase (BACE1, PDB ID: 6EJ3); essential active site residues are highlighted in red.

Fig 3. Ligand protein interaction of (A) Compound 1 (red) with acetylcholinesterase (AChE), (B) Compound 1 (red) with β-secretase (BACE1), (C) Standard donepezil (orange) with AChE, and (D) Standard elenbecestat (orange) with BACE1.

Fig 4. Ligand-protein interaction of (A) Compound 2 (Yellow) with acetylcholinesterase (AChE), (B) Compound 2 (Yellow) with β-secretase (BACE1), (C) Compound 3 (Pink) with AChE, and (D) Compound 3 (Pink) with BACE1.

Fig 5. Superimposed structure of (A) native (yellow) and re-docked B7T (green), (B) native (yellow) and re-docked donepezil (green), (C) pharmacophore model with receptor acetylcholinesterase (AChE, PDB: 6O4W), and (D) pharmacophore model with receptorβ-secretase (BACE1, PDB: 6EJ3) generated by ZINC Pharmer.

Hydrogen bond acceptors are depicted as orange spheres, hydrogen bond donors as white spheres, hydrophobic characteristics as green spheres, and aromatic rings as purple spheres.

Fig 6. Structural chemistry of 10 ursane-type triterpene saponins as dual inhibitors of acetylcholinesterase (AChE) and β-secretase (BACE1).

Fig 7. Molecular Docking (MD) simulation trajectory plot of acetylcholinesterase (AChE) and β-secretase (BACE1) exploring molecular variation with the calculation of protein backbone root mean square deviation (RMSD) of each ligand-protein complex and root mean square fluctuation (RMSF) of the free protein.

(A) Superposition of the three ligands (compound 6, 8, and donepezil) highlighting increased molecular stability for the inhibitors compound 6 and donepezil, with stability peaking after 20 ns for compound 8. (B) compound 23, compound 6, and compound 8 for the system BACE1, with low deviation in RMSD for the compounds 23 and 8. (C) RMSF calculation for protein AChE shows the regions of flexibility and rigidity of the structural dynamics in 100 ns, and (D) RMSF calculation for protein BACE1.

Fig 8. Projection of the atoms of the acetylcholinesterase (AChE) andβ-secretase (BACE1) proteins in physical motion in the binding of hydrogen interactions in 100 ns.

(A) AChE with compound 6; (B) AChE with compound 8; (C) AChE with Donepezil; (D) BACE1 with compound 6; (E) BACE1 with compound 8; (F) BACE1 with compound 23.

Fig 9. Distribution panel of short-range Coulombic interaction energy and short-range Lennard-Jones energy for both systems: acetylcholinesterase (AChE, PDB: 6O4W) andβ-secretase (BACE1, PDB: 6EJ3).

(A) The 6ej3-cp6 system obtained a Coulomb interaction energy of −57.57 kJ/mol and a Lennard-Jones energy of −70.68 kJ/mol, with a total energy of −128.25 kJ/mol. (B) The 6ej3-cp8 system obtained a Coulomb interaction energy of −82.30 kJ/mol and a Lennard-Jones energy of −188.45 kJ/mol, with a total energy of −270.75 kJ/mol. (C) The 6ej3-cp23 system obtained a Coulomb interaction energy of −25.71 kJ/mol and a Lennard-Jones energy of −114.44 kJ/mol, with a total energy of −140.15 kJ/mol. (D) Whereas the 6o4w-cp6 system obtained a Coulomb interaction energy of −209.28 kJ/mol and a Lennard-Jones energy of −196.71 kJ/mol, with a total energy of −405.99 kJ/mol. (E) For the 6o4w-cp8, we obtained a Coulomb interaction energy of −81.01 kJ/mol and a Lennard-Jones energy of −283.49 kJ/mol, with a total energy of −364.05 kJ/mol. (F) Finally, the 6o4w-Donepe obtained a Coulomb interaction energy of −41.74 kJ/mol and a Lennard-Jones energy of −188.54 kJ/mol, with a total energy of −230.28 kJ/mol. cp6: compound 6; cp8: compound 8; cp23; Compound 23 (standard); Donep: Donepezil (standard).

Fig 10. Comparison of the 2D projection of the two eigenvectors corresponding to the conformational fluctuations of the receptor systems: acetylcholinesterase (AChE, PDB:6O4W) and β-secretase (BACE1, PDB: 6EJ3), BACE1-compound 23 (A); BACE1-compound 6 (B); BACE1-compound 8 (C); AChE-donepezil (D); AChE-compound 6 (E); AChE-compound 8 (F).

Fig 11. The Gibbs free energy landscape for acetylcholinesterase (AChE) andβ-secretase (BACE1), plotted using PC1 and PC2, illustrates lower energy systems as represented by deeper blue regions on the contour map.

BACE1-compound 23 (A); BACE1-compound 6 (B); BACE1-compound 8 (C); AChE-Donepezil (D); AChE-compound 6 (E); AChE-compound 8 (F). G: Gibbs free energy (kJ/mol); PC1: Principal Component 1; PC2: Principal Component 2.