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.
Zhong et al. (Fri,) studied this question.