Computational screening of natural product inhibitor stargeting the MDM2-p53 interaction: docking and molecular dynamics insights for retinoblastoma therapy.

OBJECTIVES: To identify potential natural-product-derived inhibitors of the MDM2-p53 interaction for retinoblastoma therapy through an integrated computational screening strategy and to evaluate their binding stability, pharmacokinetic properties, and electronic characteristics. METHODS: The crystal structure of MDM2 (PDB ID: 3VZV) was validated using ERRAT and Ramachandran plot analyses. A curated natural compound library from the COCONUT database was screened by molecular docking using PyRx. Top-ranked compounds were evaluated through ADMET and toxicity prediction using SwissADME and Protox 3.0. The selected lead compound, Pentamorphone, was further investigated by 500-ns molecular dynamics simulations, MM/GBSA and MM/PBSA binding free-energy calculations, and density functional theory (DFT) analyses. RESULTS: Pentamorphone demonstrated favorable binding within the MDM2 hydrophobic pocket and exhibited acceptable pharmacokinetic and toxicity profiles. Molecular dynamics simulations confirmed the stability of the MDM2-Pentamorphone complex, as evidenced by stable RMSD, RMSF, radius of gyration, and persistent hydrogen-bond interactions throughout the 500-ns trajectory. Binding free-energy calculations indicated thermodynamically favorable complex formation, with MM/GBSA and MM/PBSA energies of -60.41 and -58.72 kcal/mol, respectively. DFT analysis revealed a HOMO-LUMO energy gap of 3.96 eV, supporting the compound's electronic stability and potential for favorable target interactions. CONCLUSIONS: The integrated computational analyses identified Pentamorphone as a promising candidate capable of disrupting the MDM2-p53 interaction. These findings support its further experimental evaluation as a potential therapeutic lead for retinoblastoma characterized by MDM2-mediated suppression of p53.