Triazole-stapled p53 mimetics as MDM2 inhibitors: structural and thermodynamic origin of enhanced binding affinity

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• The p53-MDM2 protein complex is a key target in oncogenic therapies.
• Disrupting this interaction is therapeutically challenging.
• Stapled peptides, especially triazole-based ones, offer enhanced stability and binding affinity as potential inhibitors.

Purpose of the Study:

• To investigate the binding mechanism and thermodynamics of triazole-based stapled p53 peptides with MDM2.
• To identify promising peptide variants for targeting the p53-MDM2 interaction.
• To understand the role of water molecules in the binding process.

Main Methods:

• Construction and refinement of peptide models.
• Extensive molecular simulations to analyze peptide-MDM2 binding.
• Evaluation of binding free energy and non-covalent interactions.
• Analysis of the role of water molecules in mediating interactions.

Main Results:

• The p53^4-11 peptide exhibited the most favorable binding free energy among the studied variants.
• Favorable binding of p53^4-11 is attributed to extensive non-covalent interactions, consistent with experimental data.
• Water molecules play a significant role in bridging interactions between p53 and MDM2, particularly in the p53^4-11 complex.

Conclusions:

• Triazole-stapled peptides are effective inhibitors of the p53-MDM2 interaction.
• The p53^4-11 peptide is a promising candidate for further development.
• Understanding water-mediated interactions is crucial for designing next-generation stapled peptide therapeutics.