Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by loss of dopaminergic neurons, oxidative stress, and mitochondrial dysfunction. The available interventions, such as levodopa, are mainly symptomatic in nature and do not halt disease progression. The aim of the current study was to systematically evaluate the multi-target neuroprotective potential of Portulaca oleracea L . against Parkinson disease using an integrated computational framework. Unlike previous network pharmacology docking studies on medicinal plants for Parkinson’s disease, this study introduces a structured prioritization strategy that explicitly integrates docking affinity with ADMET-based pharmacokinetic evaluation, combined with target-specific molecular dynamics (MD) simulation. Notably, MD simulation was selectively applied to the SLC6A3-hesperidin complex to provide dynamic validation of dopaminergic target engagement. A total of 62 phytochemicals reported from P. oleracea were screened, of which six compounds were selected based on oral bioavailability and drug-likeness criteria. Target prediction and network analysis identified 25 overlapping targets between compound-associated proteins and PD-relevant genes, suggesting coordinated modulation of key neurodegenerative pathways. The network analysis demonstrated that the main hub regulators of the processes involved in apoptotic signaling were GSK3B, HRAS, and SLC6A3, which are involved in dopaminergic neurotransmission. Functional enrichment analysis revealed significant involvement of MAPK, TNF, and neurotrophins signaling pathways associated with neuronal survival, apoptosis regulation, and neuroinflammation . Docking analysis revealed strong binding affinities of hesperidin and other flavonoids to these targets; particularly, hesperidin had the highest affinity (–10.3 kcal/mol with SLC6A3). In addition, molecular dynamics analysis was carried out on the SLC6A3 hesperidin complex to evaluate interaction stability at a dopaminergic target, an area that remains underexplored in prior research on P. oleracea and flavonoid-based strategies for PD. Hesperidin was selected for molecular dynamics analysis to assess structural stability and binding-related conformational behavior, while ADMET evaluation indicated that isorhamnetin exhibits more favorable pharmacokinetic characteristics, highlighting that binding affinity and pharmacokinetic suitability represent complementary rather than conflicting criteria in candidate selection. Consistently, while hesperidin demonstrated stronger target-binding interactions, isorhamnetin indicated superior pharmacokinetic characteristics, complementary roles in lead optimization and pharmacokinetic suitability. In summary, the computational results indicate that flavonoids from P. oleracea could be involved in modulating multiple PD-related pathways; however, their therapeutic relevance must be confirmed through experimental investigation.
Ali et al. (Mon,) studied this question.
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