Comparative In silico and In vitro Studies of Novel Zinc/Tin Metal Coordinates Bearing BRCA-1 Mimetics on WTp53 and MTp53 Proteins.

PURPOSE: This study compares the activity of BRCA-1 mimetics on WTp53 (wild-type p53 protein) and MTp53 (mutated-type p53 protein) proteins, examining the impact of TP53 mutations in breast cancer. p53 activators can be a new insight and synthesis of effective compounds for the treatment of cancer. The project contributes to the growing body of research on p53 activators and provides new insights into the design and synthesis of effective compounds for the treatment of cancer.

METHODS

Molecular docking predicted binding affinity values for WTp53 and MTp53. The MMGBSA of top compounds was run to get binding-free energies. The MD simulations were calculated, and six metal coordinates were synthesized. In vitro MTT-assays were performed with WTp53 (MCF-7) and R273H-MTp53 (MDA-MB-468) cell lines, comparing results with known p53 activator PRIMA-1 (p53-reactivation and induction of massive apoptosis-1).

RESULTS

The p53 activators established a three-featured (2RA, 1HBA) pharmacophore. The designed compounds had better Glide gscore compared to p53 activators PRIMA-1, PRIMA-1- MET (methylated PRIMA-1), and Tamoxifen with p53 protein (WTp53, R175H and R273H MTp53). The MM-GBSA results of top compounds showed binding free energies with R175HMTp53 (-22.24 to -75.45 kcal/mol), R273H-MTp53 (-22.8 to -36.36 kcal/mol), and WTp53 (-26.45 to -50.3 kcal/mol) compared to the p53 activator. The MD simulation of TSCO5/3KMD-MT in 100 ns indicated a stable complex when compared to TSCO5/3KMD-WT. The six metal coordinates (TSCO5-Zn, TSCO6-Zn, TSCO6-Sn, TSCO13-Zn, TSCO13-Sn, TSCO9-Sn) were synthesised. Based on in vitro results, IC50 for TSCO5-Zn (WTp53: 0.089 μM, MTp53: 0.074 μM) and TSCO5- Sn (WTp53: 0.092 μM, MTp53: 0.073 μM) have shown significant cytotoxicity.

CONCLUSION

As compared to PRIMA-1, the designed compound TSCO5 metal coordinates have shown good in silico and in vitro activity on mutated p53 cell lines and are more potent than the p53 activator PRIMA-1.