FDA-Approved Drug Repurposing as p53 Mutants Rescue Candidates Using Structure-Based Virtual Screening and Molecular...

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• Mutant p53 protein is a significant target in cancer therapy due to its role in tumor development.
• Restoring mutant p53 stability is a promising therapeutic strategy.

Purpose of the Study:

• To identify FDA-approved drugs that can stabilize mutant p53 using computational approaches.
• To nominate candidate drugs for experimental validation in cancer treatment.

Main Methods:

• Structure-based virtual screening of FDA-approved compounds against p53 mutants (7DHY, 7DHZ, 7V97).
• Molecular dynamics simulations to assess binding affinities and conformational stability.
• Protein-ligand interaction profiling and principal component analysis.

Main Results:

• DB09280 demonstrated strong binding potential and a dense interaction network with p53 mutants.
• Molecular dynamics simulations indicated DB09280 acts as a conformational clamp, reducing structural fluctuations.
• DB09280 restricted mutant p53 conformational sampling into a stable basin.

Conclusions:

• DB09280 is nominated as a promising candidate for stabilizing mutant p53.
• Further experimental validation is required to confirm functional rescue of p53 activity and tumor-suppressor function.