Therapeutic potential of curcuminoids in type 2 diabetes mellitus (T2DM): Insights from network pharmacology, molecular docking, and dynamics simulations

This study investigates the theraupetic potential of bioactive components of Curcuma longa (turmeric) for managing Type 2 Diabetes Mellitus (T2DM). A comprehensive literature review identified 10 key curcuminoid compounds, which were analyzed for their molecular interactions with T2DM related targets. A total of 437 overlapping targets between curcuminoids and diabetes-related genes were found. The interaction of protein-protein analysis highlighted 22 core targets, including AKT1, TNF, IL6, and EGFR. The fuctional annotation analysis using GO and KEGG pathway indicated that curcuminoids modulate oxidative stress, apoptosis, and insulin receptor signaling, significantly enriching the AGE-RAGE and PI3K-Akt pathways. Molecular docking simulations assessed the binding interactions between curcuminoids and the identified targets, revealing significant binding to 15 targets. Among these, Bis-demethoxyCurcumin exhibited strong binding with the GSK3B protein (7.14 kcal/mol), while DihydroCurcumin exhibited strong binding with the PI3KCA protein (−7.49 kcal/mol). Also, HexahydroCurcuminol showed favorable interactions with MAPK3 (−7.47 kcal/mol) and HexahydroCurcumin showed favorable interactions with PPARG protein (−8.17 kcal/mol). We conducted molecular dynamics simulations to further validate these interactions, thus confirming the stability of the most promising protein-ligand complexes. Bis-demethoxyCurcumin- GSK3B DihydroCurcumin-PIK3CA, HexahydroCurcuminol-MAPK3, and HexahydroCurcumin-PPARG complexes exhibited remarkable stability with average RMSD value between 2.4 Å −2.8 Å and favorable interactions during the simulation. These results suggest that curcuminoids may effectively target key molecular pathways involved in T2DM, offering significant therapeutic potential for diabetes management and drug development.