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Computational identification of potential natural terpenoid inhibitors of MDM2 for breast cancer therapy: molecular
Eva Azme1, Md Mahmudul Hasan1, Md Liakot Ali1
1Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh.
Background:
Breast cancer (BC) remains a leading cause of cancer-related mortality in women. The oncoprotein MDM2 negatively regulates the tumor suppressor p53, and its overexpression in BC promotes tumor progression and resistance to therapy. Targeting the MDM2-p53 interaction represents a promising therapeutic approach. However, many existing MDM2 inhibitors suffer from poor pharmacokinetics and off-target toxicity, necessitating the discovery of novel, more selective alternatives. This study aims to identify natural terpenoid compounds with potent MDM2 inhibitory potential through computational approaches.
Methods:
A library of 398 natural terpenoids was sourced from the NPACT database and filtered based on Lipinski's Rule of Five. A two-stage docking strategy was applied: 1) rigid protein-flexible ligand docking to screen for high-affinity binders, followed by 2) ensemble docking using multiple MDM2 conformations derived from molecular dynamics (MD) simulations. The top candidates were further evaluated for their pharmacokinetic and toxicity profiles using ADMET analysis. Finally, 150 ns MD simulations and binding free energy (MM-PBSA) calculations were performed to assess the stability and strength of protein-ligand interactions.
Results:
Three terpenoid compounds, olean-12-en-3-beta-ol, cabralealactone, and 27-deoxyactein demonstrated strong binding affinities toward MDM2 in ensemble docking studies. ADMET analysis confirmed their favorable pharmacokinetic properties. Further MD simulations indicated that these compounds formed highly stable complexes with MDM2. Notably, 27-deoxyactein exhibited the lowest binding free energy (-154.514 kJ/mol), outperforming the reference inhibitor Nutlin-3a (-133.531 kJ/mol), suggesting superior binding stability and interaction strength.
Conclusion:
Our findings highlight 27-deoxyactein as a promising MDM2 inhibitor with strong binding affinity, stability, and a favorable pharmacokinetic profile. This study provides a computational foundation for further experimental validation, supporting the potential of terpenoid-based MDM2 inhibitors in BC therapy.
Insights
This study identified natural terpenoids as potential breast cancer (BC) therapeutics by computationally targeting the MDM2 oncoprotein. 27-deoxyactein showed superior binding affinity and stability, offering a promising new avenue for BC treatment.
Area of Science:
- Oncology
- Computational Chemistry
- Pharmacology
Background:
- Breast cancer (BC) is a leading cause of cancer mortality in women.
- MDM2 oncoprotein overexpression in BC promotes tumor progression and therapy resistance.
- Targeting the MDM2-p53 interaction is a promising therapeutic strategy, but existing inhibitors have limitations.
Purpose of the Study:
- To identify novel natural terpenoid compounds with potent MDM2 inhibitory potential using computational approaches.
- To evaluate the binding affinity, pharmacokinetic properties, and stability of identified terpenoids.
- To provide a computational basis for developing new BC therapies.
Main Methods:
- A library of 398 natural terpenoids was screened using Lipinski's Rule of Five.
- A two-stage docking strategy (rigid protein-flexible ligand and ensemble docking) was employed.
- ADMET analysis, molecular dynamics (MD) simulations, and MM-PBSA calculations were performed for top candidates.
Main Results:
- Three terpenoids—olean-12-en-3-beta-ol, cabralealactone, and 27-deoxyactein—showed strong binding affinities to MDM2.
- ADMET analysis indicated favorable pharmacokinetic properties for these compounds.
- 27-deoxyactein exhibited the lowest binding free energy (-154.514 kJ/mol), outperforming the reference inhibitor Nutlin-3a.
Conclusions:
- 27-deoxyactein is a promising MDM2 inhibitor with high binding affinity, stability, and favorable pharmacokinetics.
- This study provides a computational foundation for experimental validation of terpenoid-based MDM2 inhibitors for BC therapy.
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