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.