In Silico Screening of Inhibitors of p53-MDM2 Protein Complex through Homology Modelling and Molecular docking

The p53 protein is a tumour suppressor crucial in the apoptotic pathway where regulated the cell cycle and its function is regulated by direct binding to MDM2 protein. Therefore, inhibition of p53-MDM2 interaction leads to activation of p53's tumour suppressing function and presented novel therapeutic strategy against several types of cancers. In this study, homology modelling was done to derive three-dimensional structure of p53 and MDM2 proteins, after which macromolecular docking was performed to obtain p53-MDM2 complex. Hex docking software was utilized to screen ZINC chemical database for small molecule p53-MDM2 inhibitors through molecular docking using shape complementarity function, subjected database to filter conditions suggested by Lipinski's rules to reduce library to manageable subset. The screened ligands were ligands were ranked according to free energy scoring function. The result found that top ranking compound was benzoyl-[3-(trifluoromethyl)phenyl]-BLAHdione which gave a score of -7.693 kcal/mole. This compound which had aromatic moieties interacting with nonpolar regions of complex and region constituted by sp(3)-hybridized carbon rendering flexibility of binding mode which served as starting point for further modifications to advance design of drugs would inhibit the protein interaction.