Evaluating the inhibitory efficacy of Oxalis phytocompounds on monoamine oxidase B: An integrated approach targeting age related neurodegenerative diseases through molecular docking and dynamics simulations

Abstract

Monoamine oxidase B (MAO-B) serves as a critical target in the management of neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's due to its role in regulating oxidative stress and dopamine metabolism. In this context, phytochemicals from Oxalis species, known for their neuroprotective properties, were explored for their potential MAO-B inhibitory activity using computational approach. Plant-derived compounds, offering a better safety profile than synthetic drugs and greater cost-effectiveness, present a promising avenue for developing alternative therapeutic strategies. Molecular docking (MD), molecular dynamics simulations (MDS), and binding free energy calculations were employed to evaluate the inhibitory potential of Oxalis phytochemicals against MAO-B (PDB ID: 4A79). Stable ligand-protein complexes with optimal docking scores were selected, and key parameters from molecular dynamics trajectories, including binding stability and interactions, were analyzed to identify high potential inhibitors of MAO-B for therapeutic development. Results showed beta-sitosterol (-11.92 kcal/mol), squalene (-11.89 kcal/mol), etretinate (-11.46 kcal/mol), rhoifolin (-11.44 kcal/mol), and swertisin (-11.13 kcal/mol) demonstrated superior binding affinities compared to the native ligand (-11.12 kcal/mol). Three additional compounds; phloridzin (-11.10 kcal/mol), rhapontin (-11.02 kcal/mol), and diosmetin 7-O-beta-D-glucopyranoside (-10.96 kcal/mol) exhibited better binding than reference drugs. The predominant interactions between protein and ligand were hydrophobic, with hydrogen bonds and Pi-stacking enhancing the complexes' stability. The evaluation based on geometrical and thermodynamic metrics derived from 200 ns MDS, identified rhoifolin, beta-sitosterol, and swertisin as promising MAO-B inhibitors. Minimal translational and rotational movements of these ligands within the catalytic site of MAO-B under quasi-physiological conditions suggested effective inhibition. Preserved thermodynamic feasibility reinforced these findings. ADMET analysis identified squalene and beta-sitosterol as CNS active candidates with favorable pharmacokinetics, while etretinate, rhoifolin, and swertisin may act as peripheral modulators, requiring optimization for improved CNS delivery. Further experimental validation of efficacy, pharmacokinetics, and safety is recommended to advance the therapeutic potential of these hit candidates.

Fig 1. Monoamine Oxidase-B (MAO-B) enzyme structure in its holo form depicted in ribbon representation, with native ligand P1B, Pioglitazone, shown as bond line model at the orthosteric site.

Fig 2. Superimposition of docked ligand (green) derived from the molecular docking calculations, with the native ligand (cyan) present in the crystal structure (heavy atom RMSD = 0.768 Å).

Fig 3. Chemical structures of top 8 phytochemicals from Oxalis species identified based on molecular docking scores against MAO-B enzyme.

Fig 4. Visualization of the top five protein-ligand adducts at various time points during molecular dynamics simulations, highlighting the dynamical nature of the ligand relative to the protein structure and also of the protein geometry around the active site.

Fig 5. RMSD of top 8 ligands relative to protein backbone obtained from MDS trajectories of different complexes (violet = beta-sitosterol, green = squalene, red = etretinate, cyan = rhoifolin, magenta = swertisin, blue = phloridzin, orange = rhapontin, maroon = diosmetin-7-O-beta-D-glucopyranoside).

Fig 6. RPDF plot depicting the center of mass between the top 8 ligands and the protein within these complexes extracted from the MDS trajectories; a distinct sharp peak indicates the ligand’s localized positioning; Complex 1 (violet); Complex 2 (green); Complex 3 (red); Complex 4 (cyan); Complex 5 (magenta); Complex 6 (blue); Complex 7 (orange); Complex 8 (maroon).

Fig 7. Changes in D-A atom distances in hydrogen bonds observed during the MDS trajectory for protein-ligand complex with swertisin, involving HIS90 and the oxygen acceptor of the ligand.

Fig 8. Changes in D-A atom distances in hydrogen bonds observed during the MDS trajectory for protein-ligand complex with swertisin, involving TYR435 and the oxygen acceptor of the ligand.