Structure-Guided Virtual Screening and Molecular Dynamics Simulation of Selective Small-Molecule Inhibitors Targeting E3 Ubiquitin Ligase MDM2 in Breast Cancer

Background

MDM2 is an E3 ubiquitin ligase that suppresses p53, promotes its degradation, inhibits apoptosis, and drives uncontrolled cancer cell growth. Targeting the MDM2-p53 interaction is therefore a promising strategy for solid tumor therapy.

Purpose

To identify selective small-molecule MDM2 inhibitors with potential therapeutic value in breast cancer.

Materials and Methods

A structure-based virtual screening workflow was performed on the MCULE platform. Selected hits were assessed using PASS, cell line prediction, safety, pharmacokinetic, and ADMET analyses, followed by molecular dynamics simulations to evaluate complex stability.

Results

Virtual screening identified promising MDM2-targeting compounds. Subsequent profiling highlighted two lead candidates with predicted cytotoxic activity, favorable drug-like properties, and stable binding within the MDM2 pocket.

Conclusion

Two potential small-molecule MDM2 inhibitors were identified as promising lead compounds for restoring p53 activity and developing targeted breast cancer therapies.