Proposing novel MDM2 inhibitors: Combined physics-driven high-throughput virtual screening and in vitro studies

Area of Science:

• Oncology
• Medicinal Chemistry
• Computational Biology

Background:

• The mouse double minute 2 (MDM2) protein is a key negative regulator of the p53 tumor suppressor, promoting p53 ubiquitination and degradation.
• MDM2-mediated p53 suppression is a common mechanism in cancer, making it a significant therapeutic target.
• Developing novel MDM2 inhibitors is crucial for cancer therapy.

Purpose of the Study:

• To identify novel small organic molecules that inhibit the MDM2 oncogenic target.
• To evaluate the therapeutic potential and pharmacokinetic properties of identified inhibitors.
• To validate the efficacy of selected compounds against human cancer cell lines.

Main Methods:

• High-throughput virtual screening of approximately 500,000 small molecules from the Enamine database against the MDM2 binding pocket.
• Docking simulations, binary quantitative structure-activity relationship (QSAR) models, and all-atom molecular dynamics simulations.
• In vitro studies using HUVEC, colon cancer, and breast cancer cell lines to assess binding affinity, cellular effects, proliferation inhibition, and apoptosis induction.

Main Results:

• Virtual screening identified 100 hits, which were further refined using QSAR and molecular dynamics simulations.
• Eleven compounds (E1-E11) were selected for in vitro validation based on computational analyses.
• Six compounds demonstrated significant activity against breast cancer cell lines and six against colon cancer cell lines, inhibiting proliferation and inducing apoptosis.

Conclusions:

• The study successfully identified novel MDM2 inhibitors with potential anti-cancer activity.
• Selected compounds show promise in inhibiting cancer cell proliferation and inducing apoptosis in vitro.
• These findings provide a basis for further development of MDM2-targeted cancer therapies.