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<p>Neurodegenerative disorders such as Parkinson’s disease (PD) arise from interconnected mechanisms including mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired protein homeostasis, leading to progressive dopaminergic neuron loss and limited benefit from current single target therapies. Parkin (PARK2), an E3 ubiquitin ligase central to mitochondrial quality control and mitophagy, has therefore emerged as an attractive therapeutic node, with its functional stabilization representing a promising strategy to restore mitochondrial homeostasis in PD. In this study, phytocompounds from <i>Althaea officinalis</i> were evaluated using an integrated in silico pipeline combining ADMET prediction, molecular docking, 100 ns molecular dynamics simulations, MM-GBSA binding free energy analysis, and network pharmacology to identify potential PARK2 modulating lead compounds relevant to Parkinson’s disease. Forty bioactive constituents were screened, and computational ADMET modeling highlighted flavonoids and coumarin derivatives such as scopolin, astragalin, isoquercitrin, and quercetin derivatives as having acceptable oral absorption, limited predicted toxicity, and low risk of major metabolic or cardiotoxic liabilities. Structure-based docking against PARK2 (PDB ID: 5C23) revealed that several <i>A. officinalis</i> metabolites, notably scopolin, β-D-glucose, quercetin-3-glucoside, and L-arabinose, exhibit favorable binding affinities (docking scores − 7.232 to − 6.648&#xa0;kcal/mol) and form energetically stable complexes with key catalytic and regulatory residues, in some cases outperforming co-crystal ligand. Subsequent 100 ns molecular dynamics simulations confirmed that the scopolin– and quercetin-3-glucoside–PARK2 complexes remain structurally stable, with low RMSD fluctuations, compact Rg profiles, and persistent hydrogen-bonding, while MM-GBSA calculations yielded consistently favorable ΔGbind values, further supporting their high-affinity interaction with PARK2. Network pharmacology analysis further showed that these phytochemicals converge on core PD-related targets such as AKT1, PIK3R1, MAPT, SNCA, PSEN2, BCL2L1, HK1, RPS6KA3, TLR1, and TLR2 within PI3K–Akt, MAPK, mTOR, HIF-1, autophagy, apoptosis, insulin, Toll-like receptor, and Parkinson disease pathways, indicating a multi-target, multi-pathway mode of action. Overall, the findings suggest that <i>A. officinalis</i> phytocompounds especially scopolin and quercetin glycosides possess drug-like ADMET properties, strong PARK2 binding, MD-validated complex stability with favorable MM-GBSA binding energies, and systems-level engagement with PD-relevant signaling networks, supporting their candidacy as plant-derived leads for PARK2-centered therapeutic strategies in PD.</p>

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Integrated in silico docking, ADMET, and network pharmacology evaluation of Althaea officinalis L. phytocompounds targeting Park2 for the management of Parkinson’s disease

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • M. Heshetha,
  • Muthineni Haneesh,
  • Venkatesan Karthick,
  • Rajkumar Thamarai,
  • Singamoorthy Amalraj

摘要

Neurodegenerative disorders such as Parkinson’s disease (PD) arise from interconnected mechanisms including mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired protein homeostasis, leading to progressive dopaminergic neuron loss and limited benefit from current single target therapies. Parkin (PARK2), an E3 ubiquitin ligase central to mitochondrial quality control and mitophagy, has therefore emerged as an attractive therapeutic node, with its functional stabilization representing a promising strategy to restore mitochondrial homeostasis in PD. In this study, phytocompounds from Althaea officinalis were evaluated using an integrated in silico pipeline combining ADMET prediction, molecular docking, 100 ns molecular dynamics simulations, MM-GBSA binding free energy analysis, and network pharmacology to identify potential PARK2 modulating lead compounds relevant to Parkinson’s disease. Forty bioactive constituents were screened, and computational ADMET modeling highlighted flavonoids and coumarin derivatives such as scopolin, astragalin, isoquercitrin, and quercetin derivatives as having acceptable oral absorption, limited predicted toxicity, and low risk of major metabolic or cardiotoxic liabilities. Structure-based docking against PARK2 (PDB ID: 5C23) revealed that several A. officinalis metabolites, notably scopolin, β-D-glucose, quercetin-3-glucoside, and L-arabinose, exhibit favorable binding affinities (docking scores − 7.232 to − 6.648 kcal/mol) and form energetically stable complexes with key catalytic and regulatory residues, in some cases outperforming co-crystal ligand. Subsequent 100 ns molecular dynamics simulations confirmed that the scopolin– and quercetin-3-glucoside–PARK2 complexes remain structurally stable, with low RMSD fluctuations, compact Rg profiles, and persistent hydrogen-bonding, while MM-GBSA calculations yielded consistently favorable ΔGbind values, further supporting their high-affinity interaction with PARK2. Network pharmacology analysis further showed that these phytochemicals converge on core PD-related targets such as AKT1, PIK3R1, MAPT, SNCA, PSEN2, BCL2L1, HK1, RPS6KA3, TLR1, and TLR2 within PI3K–Akt, MAPK, mTOR, HIF-1, autophagy, apoptosis, insulin, Toll-like receptor, and Parkinson disease pathways, indicating a multi-target, multi-pathway mode of action. Overall, the findings suggest that A. officinalis phytocompounds especially scopolin and quercetin glycosides possess drug-like ADMET properties, strong PARK2 binding, MD-validated complex stability with favorable MM-GBSA binding energies, and systems-level engagement with PD-relevant signaling networks, supporting their candidacy as plant-derived leads for PARK2-centered therapeutic strategies in PD.