Flavonoids as potential reactivators of structural mutation p53Y220C by computational and cell-based studies

Abstract

The p53 Y220C is one of the most frequently observed structural mutants in various human cancers. The substitution of residue Tyr to Cys makes the p53 DNA binding domain susceptible to solvent entry into the hydrophobic core of the domain thereby destabilizing p53, which results in loss of its tumor suppressor activity. The mutation creates a structural crevice at the region between S3/S4 and S7/S8 loops in the DNA binding domain which can be targeted by small molecules. Studies have shown that the synthetic and natural compounds could bind to this crevice and restore the structure and function of the mutant p53Y220C to the wild type. In our previous study, we have shown Curcumin could rescue the function of mutant p53Y220C in pancreatic cancer cell line BxPC-3 harboring genomic mutation. In this study, we explored six flavonoids structurally similar to Curcumin such as Apigenin, Isoliquiritigenin, Liquiritigenin, Luteolin, Methylophiopogonanone A (MPA), and Methylophiopogonanone B (MPB) to test their potency to restore p53Y220C by molecular docking, molecular dynamics simulations and cytotoxicity assay. The secondary structure analysis after the MD simulations suggested that these compounds could stabilize the mutant p53 DNA binding domain to the wild type. In the cell-based cytotoxicity studies using p53Y220C harbouring BxPC-3 cell lines, the compounds MPA and MPB showed 75% cell death at 100 µM concentration. We proposed that the flavonoids MPA and MPB have the therapeutic potential to restore p53Y220C and could be used as a combinatorial therapy to reduce the dosage burden. Communicated by Ramaswamy H. Sarma