Network toxicology-driven repurposing of metformin for hepatocellular carcinoma: insights from molecular docking and dynamics simulations
Abstract
Context: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality with limited therapeutic options and poor prognosis, particularly in advanced stages. This study integrates computational and experimental approaches to evaluate metformin as a candidate for repurposing in HCC. Key oncogenic targets EGFR, MAPK3, MMP9, and PRKACA were prioritized via protein-protein interaction network analysis. Molecular docking predicted favorable metformin binding poses for EGFR (ΔG = -7.42 kcal/mol), MAPK3 (ΔG = -7.45 kcal/mol), MMP9 (ΔG = -7.84 kcal/mol), and PRKACA (ΔG = -8.33 kcal/mol). Using AmberTools/Antechamber-derived GAFF2 parameterization and AM1-BCC partial charges for ligand topology, repeated 100 ns molecular dynamics simulations showed ligand retention with target-specific receptor and pocket RMSD adaptation and stable radius-of-gyration profiles. Network toxicology predicted low hepatotoxicity risk using ProTox-II and ADMETlab 2.0 endpoints. ITC measurements produced detectable metformin-protein binding responses and apparent dissociation constants under the reverse-orientation assay conditions (20 µM protein in the cell and 200 µM metformin in the syringe). Western blot analysis showed reduced total EGFR, MAPK3, and MMP9 expression after metformin treatment, while PRKACA changed only slightly. Triplicate MTT assays showed concentration-dependent inhibition of HepG2 cell viability, with an IC50 of 16.02 µM.
Methods: Metformin and HCC-associated…
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