Investigating the Effect of Metformin on p53 Protein Using a Molecular Docking Approach

Abstract

Background: The tumor suppressor protein p53 plays a fundamental role in maintaining genomic stability by regulating the cell cycle, DNA repair, and apoptosis. Metformin, a widely prescribed antidiabetic drug, has demonstrated potential anticancer properties, but the exact molecular mechanisms underlying its effects remain fully elucidated. This study explored the molecular interaction between metformin and the p53 protein using a computational molecular docking approach to understand better how metformin may influence p53’s tumor-suppressive functions. Materials and Methods: The crystal structure of human p53 (PDB ID: 1KZY) was prepared using UCSF Chimera, and metformin’s structure was optimized via OpenBabel and Chimera. Binding site prediction was performed using DeepSite, and molecular docking simulations were conducted with AutoDock Vina in PyRx. Interaction analyses were performed in UCSF Chimera, PyMOL, and PDBsum to identify hydrogen bonds, hydrophobic interactions, and electrostatic interactions. Results: The docking analysis indicated that metformin binds to p53 with a high binding affinity of −8.6 kcal/mol. Hydrogen bonds with Ar273 (2.5 Å) and Glu285 (2.8 Å), hydrophobic interactions with Asp281, Val272, and Phe270, and electrostatic interactions with Lys120. Nine binding poses were analyzed, suggesting that metformin may bind flexibly to the p53 binding pocket. The residues involved are critical for DNA binding and structural stability, indicating that metformin could contribute to the stabilization and functional regulation of p53. Conclusion: This study provides computational evidence that metformin directly interacts with important functional residues of the p53 protein, supporting the hypothesis that it may enhance p53’s tumor-suppressive activity. These findings offer a molecular basis for the anticancer effects of metformin and highlight the need for further in vitro and in vivo studies to confirm and expand upon them, especially in cancers with p53-related dysregulation.