Therapeutic strategy for Parkinson's disease through MAO-B inhibition by a novel compound: MD simulation, DFT analysis and pharmacokinetic study

Research on Parkinson's disease (PD) treatment through monoamine oxidase B (MAO-B) enzyme inhibition has continued for many years. Deprenyl has been prescribed as a drug to treat the symptoms of Parkinson's disease; however, there is an urgent need for new anti-Parkinson drugs due to reduced long-term efficacy and severe side effects. Therefore, this study aimed to identify plant compounds through computational studies to identify potential MAO-B inhibitors. ADMET analysis and Lipinski filter highlighted the drug similarity and pharmacokinetic properties of the selected molecule Piperine (PIP). Molecular docking results showed the highest binding affinity with increased hydrophobic interactions for PIP compared to the co-crystal ligand. Molecular dynamics (MD) simulation results showed that PIP could be considered as a prominent candidate. PCA and FEL results recorded structural changes in the presence of PIP. PIP showed the highest number of aromatic interactions (pi–pi stacking) compared to Deprenyl, which are crucial for ligand binding. The binding free energies for PIP (−142.12 ± 11.34 kJ/mol) were significantly higher than for the co-crystal (−86.21 ± 11.15 kJ/mol), in accordance with the frontier molecular orbital energies (HOMO-LUMO) obtained from DFT results; PIP exhibited electronically softer, higher reactivity and increased molecular dipole moment than the cocrystal. Although these results can be useful in the search for new, effective, and selective MAO-B inhibitors to modify lead and develop new drugs for the treatment of Parkinson's; however, it is necessary to conduct in vitro and in vivo experiments to confirm and validate these findings in future studies.