FDA-approved drug repurposing as p53 mutants rescue candidates using structure-based virtual screening and molecular simulations

The restoration of mutant p53 stability is a highly sought-after strategy in targeted cancer therapy. This study presents a structure-based virtual screening and molecular dynamics approach to repurpose FDA-approved drugs as p53 rescue candidates. A virtual screening library of FDA-approved compounds was docked against three representative p53 mutants (7DHY, 7DHZ, and 7V97) to evaluate their binding potential. The prioritized candidates demonstrated consistent, multi-conformer binding affinities. Protein-ligand interaction profiling revealed that the candidate DB09280 possesses a highly dense interaction network, particularly against the V272M and R249S variants. Residue-level analysis of the G245S structural mutant showed that DB09280 uniquely engages His19, a crucial residue for zinc coordination, and forms stabilizing contacts with adjacent flexible loop residues, including ASN35 and PRO32. Subsequent 500 ns molecular dynamics simulations demonstrated that DB09280 acts as a conformational clamp. The ligand-bound (holo) system exhibited substantially reduced global structural drift (RMSD) and attenuated local residue fluctuations (RMSF) within the core domain compared to the highly unstable apo state. Principal component analysis further confirmed that DB09280 restricts the broad conformational sampling of the mutant into a stable, dominant energetic basin. These findings highlight DB09280 as a robust p53 stabilizer and provide a compelling mechanistic foundation for its repurposing in oncology.