Virtual screening of p53 mutants reveals Y220S as an additional rescue drug target for PhiKan083 with higher binding characteristics.

Pharmacological intervention to reactivate p53 in human tumors holds great promise for cancer patients. A number of small molecules that reactivate p53 mutants that are either specific to certain mutation or more broadly on various mutants of p53 are discovered by rational design and screening methods. One of the most remarkable among small molecules for the rescue of specific mutant p53, Y220C is PhiKan083 (1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine) that have been demonstrated effective in advanced pre-clinical trials. Our attempt here is to identify additional targets of p53 mutants for rescue drugs and provide insight into the molecular level interactions of the drug with the mutant target. In this study PhiKan083 also known as PK083 is investigated, screened and validated on 28 different mutants of p53 using FlexX. Interaction of PhiKan08 with Y220C is found to be largely hydrophobic and a crucial single H-bond interaction with Asp228 in addition to few electrostatic interactions. Our study identified Y220S mutant as an additional target for PK083 as it shows a similar interaction pattern. Besides this, Docking and MD simulation studies, showed that Y220S binds to PK083 at higher efficiency as a result of improved steric and hydrophobic environment in the binding cavity in comparison with known mutant target, Y220C. Further, we point out that structure guided optimization of PhiKan08 can lead to an improved drug that can interact favourably with yet another mutant, Y220 N. In addition, this study revealed that Y220H and other mutants including native p53 does not provide any favourable interaction with PhiKan08 which is in accord with the experimental findings. These findings can facilitate the selection of patients for clinical studies and cancer survival analysis.