PloS one · 2026
Integrative GC-MS, network pharmacology, and molecular dynamics elucidate synergistic anti-diabetic mechanisms of Chongqing Citrus reticulata 'Dahongpao' volatile oil via multi-target stabilization.
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Zhong Wanting, Xiong YaYi, Luo Jie, Ahmad Shujaat, Wang Jian
Аннотация
BACKGROUND: Diabetes mellitus involves complex pathogenesis requiring multi-target interventions. Citrus reticulata 'Dahongpao' from Chongqing exhibits anti-diabetic potential, but its mechanisms remain elusive.
METHODS: We employed an integrative strategy: GC-MS identified 82 compounds (96.61% coverage), dominated by D-limonene (62.48%). Network pharmacology revealed 36 diabetes-related targets. Molecular docking prioritized ligands (thymol: -6.8 kcal/mol with FABP1; n-hexadecanoic acid: -6.7 kcal/mol with PTGS2). Critical validation was achieved via 100-ns molecular dynamics (MD) simulations and MM-GBSA binding free energy calculations.
RESULTS: MD simulations demonstrated structural stability (RMSD < 2.5 Å) for core complexes (e.g., CYP19A1/thymol). MM-GBSA quantified robust binding for FABP1/dodecanoic acid (-43.26 kcal/mol) and PTGS2/n-hexadecanoic acid (-43.93 kcal/mol), driven by van der Waals forces. Hydrogen bond dynamics revealed persistent interactions (e.g., thymol-THR102 in FABP1), while RMSF highlighted ligand-induced flexibility in fatty acids. Pathway analysis implicated PPAR signaling and insulin resistance.
CONCLUSION: Citrus reticulata 'Dahongpao' essential oil combats diabetes through synergistic multi-target modulation, validated by dynamic ligand-protein stability and energetics. This study presents an in silico framework that integrates phytochemical profiling and computational analyses to facilitate natural product drug discovery.
METHODS: We employed an integrative strategy: GC-MS identified 82 compounds (96.61% coverage), dominated by D-limonene (62.48%). Network pharmacology revealed 36 diabetes-related targets. Molecular docking prioritized ligands (thymol: -6.8 kcal/mol with FABP1; n-hexadecanoic acid: -6.7 kcal/mol with PTGS2). Critical validation was achieved via 100-ns molecular dynamics (MD) simulations and MM-GBSA binding free energy calculations.
RESULTS: MD simulations demonstrated structural stability (RMSD < 2.5 Å) for core complexes (e.g., CYP19A1/thymol). MM-GBSA quantified robust binding for FABP1/dodecanoic acid (-43.26 kcal/mol) and PTGS2/n-hexadecanoic acid (-43.93 kcal/mol), driven by van der Waals forces. Hydrogen bond dynamics revealed persistent interactions (e.g., thymol-THR102 in FABP1), while RMSF highlighted ligand-induced flexibility in fatty acids. Pathway analysis implicated PPAR signaling and insulin resistance.
CONCLUSION: Citrus reticulata 'Dahongpao' essential oil combats diabetes through synergistic multi-target modulation, validated by dynamic ligand-protein stability and energetics. This study presents an in silico framework that integrates phytochemical profiling and computational analyses to facilitate natural product drug discovery.