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February 2, 2026Open Access

Integrated network pharmacology and molecular modeling approaches to reveal the anti-diabetic potential of phytochemicals from Zanthoxylum simulans

Key Points

The research aims to explore the anti-diabetic potential of phytochemicals from Zanthoxylum simulans using advanced computational methods.
Integrated network pharmacology with molecular docking and ADMET profiling.
Screened 120 phytochemicals to identify five leads based on docking scores.
Utilized molecular dynamics simulations (200 ns) for stability analysis.
Conducted PCA and FEL analyses to assess entropic flexibility.
Target identification using Cytoscape and STRING for diabetes-related proteins.
β-Sitostenone showed the highest docking affinities for the proteins STAT3 and PPARG.
All selected compounds exhibited favorable ADMET profiles indicating safety for further development.
Magnocurarine demonstrated superior dynamic stability compared to pioglitazone.
Binding analysis revealed consistent hydrogen bonds and compact molecular structure for the leads.

Abstract

Abstract Background Zanthoxylum simulans , traditionally used for diabetes, lacks molecular mechanistic insights. This study integrates network pharmacology, molecular docking, ADMET profiling, 200-ns molecular dynamics, PCA, and FEL analyses to identify anti-diabetic phytochemicals from its fruit and bark. Methods From 120 literature-identified phytochemicals, five leads were screened (MolSoft DL ≥ 0.18): magnocurarine (1.45), N-methyltetrahydrocolumbamine (1.30), reticuline (1.13), β-sitostenone (0.91), menisperine (0.87). SwissTargetPrediction yielded 500 targets overlapping 27 diabetes genes (DisGeNET), identifying hub proteins PPARG, IL6, TNF, STAT3 via Cytoscape/STRING. Docking used AutoDock Vina; ADMET via SwissADME/pkCSM; Molecular Dynamics (200 ns GROMACS) with RMSD/RMSF/Rg/SASA/H-bond analysis; PCA/FEL via Bio3D/OriginPro. Results β-Sitostenone showed the highest docking affinities (-8.5 kcal/mol STAT3, -8.2 kcal/mol PPARG); menisperine -8.1 kcal/mol STAT3. All leads had optimal ADMET (no hepatotoxicity/hERG inhibition; LD50 2.356–2.531 mol/kg). Magnocurarine-PPARG exhibited superior stability vs pioglitazone: stable RMSD (< 0.30 nm), low RMSF (0.05–0.15 nm), compact Rg (1.92–1.98 nm), reduced SASA (142–150 nm 2 ), consistent H-bonds (2–4), and broader FEL basic indicating entropic flexibility. Conclusion Magnocurarine emerges as a superior anti-diabetic lead from Zanthoxylum simulans , demonstrating exceptional PPARG binding, pharmacokinetic safety, and dynamic stability over 200 ns validating its therapeutic potential.

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