In silico Discovery of Dual Ligands Targeting MAO-B and AA2AR from African Natural Products Using Pharmacophore Modelling, Molecular Docking, and Molecular Dynamics Simulations

Currently available treatments for Parkinson's disease offer limited symptomatic relief to patients and do not halt the progress of the disease. Several studies have reported that the use of a multi-targeting approach for treating neurodegenerative diseases may prove more beneficial for patients. In this study, two successful drug targets for treating Parkinson's disease known for their potential to slow down neuronal loss were selected. Natural products have long been known to be effective and safe in treating various diseases. Therefore, we used computational approaches to screen the North, East, and South African Natural Products databases for novel dual-targeting drug candidates against MAO-B and AA(2A)R. A hybrid virtual screening was performed through pharmacophore modelling and molecular docking followed by ADME/Toxicity evaluation. Our results revealed two furanoisoflavones with equally favourable binding affinities and interaction profiles for MAO-B and AA(2A)R as well as desirable pharmacokinetic properties for drugs acting on the brain. Molecular dynamics simulations were conducted to assess the stability of the lead compounds and the reference drugs over time. The findings emphasized the notable stability of the suggested drugs in comparison to safinamide. Notably, 7,3'-dimethoxy-4',5'-methylenedioxyisoflavone established a crucial hydrogen bond with Gln-206, a characteristic interaction observed in most MAO-B inhibitors. Regarding AA(2A)R, while the interaction strength with Asn-253 may not match that of the reference drug, simulation results indicated a parallel trend in protein interaction, suggesting its potential as an antagonist. The findings from this study could potentially act as starting points for refining and developing natural products into disease-modifying remedies for Parkinson's disease patients. Nevertheless, it is imperative to conduct experimental assays to substantiate these discoveries.