Hydrophobic Interactions Are a Key to MDM2 Inhibition by Polyphenols as Revealed by Molecular Dynamics Simulations and MM/PBSA Free Energy Calculations

• DOI: 10.1371/journal.pone.0149014
• Publication Date: 2016-02-10T19:14:32Z
• Authors: Sharad Verma; Sonam Grover; Chetna Tyagi; Sukriti Goyal; Salma Jamal; Aditi Singh; Abhinav Grover
• Keywords: Flavonoids; 0301 basic medicine; DNA Repair; Flavonols; Science; Q; R; Molecular Conformation; Polyphenols; Antineoplastic Agents; Proto-Oncogene Proteins c-mdm2; Molecular Dynamics Simulation; 03 medical and health sciences; Medicine; Humans; Thermodynamics; Computer Simulation; Apigenin; Tumor Suppressor Protein p53; Luteolin; Hydrophobic and Hydrophilic Interactions; Research Article; Protein Binding

p53, a tumor suppressor protein, has been proven to regulate the cell cycle, apoptosis, and DNA repair to prevent malignant transformation. MDM2 regulates activity of p53 and inhibits its binding to DNA. In the present study, we elucidated the MDM2 inhibition potential of polyphenols (Apigenin, Fisetin, Galangin and Luteolin) by MD simulation and MM/PBSA free energy calculations. All polyphenols bind to hydrophobic groove of MDM2 and the binding was found to be stable throughout MD simulation. Luteolin showed the highest negative binding free energy value of -173.80 kJ/mol followed by Fisetin with value of -172.25 kJ/mol. It was found by free energy calculations, that hydrophobic interactions (vdW energy) have major contribution in binding free energy.