Inhibition of the p53 Y220C Mutant by 1-Hydroxy-2- Methylanthraquinone Derivatives: A Novel Strategy for Cancer Therapy.

Abstract

Y220C, a substitution mutation in p53, causes major structural changes in the protein and is known to form a new protein cavity. This cavity is reckoned to accommodate small drug candidates that may play a key role in cancer treatment. Present study was aimed at determining a drug candidate that could inhibit the mutant p53 based on structural drug rationale. Docking of mutated p53 was performed to determine the drug of choice from the derivatives of 1-hydroxy-2- methylanthraquinone exhibiting anti-cancer properties. The cavity had been tested for identification of an accurate position vector for molecular docking studies using structure based drug design. The docked structure was validated using discovery studio 3.5. The best choice of two molecules were obtained by docking in specific solvent for 6 nanoseconds at a temperature of 310 K. Out of a library of compounds, acetamido-2-carboxy-4-dimethylamino-2- hydroxybenzophenone satisfied the ADMET and was found to be a potential target for mutant p53. This ligand binds at the active site of the protein. Results of present study offer a rationale of the lead ligands that can rescue oncogenic p53 by targeting the mutation site. Therefore, it is suggestive that small molecules may serve as an effective and novel anti-cancer drug.