Caffeic acid phenethyl ester (CAPE) confers wild type p53 function in p53(Y220C) mutant: bioinformatics and experimental evidence

Mutations in the tumor suppressor protein p53 is a prevalent feature in majority of cancers resulting in inactivation of its activities related to control of cell cycle progression and proliferation. p53(Y220C) is one of the common hotspot mutations that causes decrease in its thermodynamic stability. Some small molecules have been shown to bind to the mutated site and restore its wild type thermodynamics and tumor suppressor function. In this study, we have explored the potential of caffeic acid phenethyl ester (CAPE—a bioactive compound from propolis) to interact with p53(Y220C) and restore its wild type p53 (p53(wt)) transcription activation and tumor suppressor activities. We recruited computational methods, viz. molecular docking, molecular dynamics simulations and free energy calculations to study the interaction of CAPE at the mutation crevice and found that it has potential to restore p53(wt) function of the p53(Y220C) mutant similar to a previously described restoration molecule PK7242. We provide cell-based experimental evidence to these predictions and suggest CAPE as a potential natural drug for treatment of p53(Y220C) mutant harboring cancers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-021-00461-2.