Molecular Modeling Investigation of Folic Acid Conjugation to MDM2 Inhibitors for Enhanced Cellular Uptake and Target Binding

The activation of tumor suppressor p53 protein through inhibition of its interaction with the oncogenic Murine Double Minute 2 (MDM2) protein presents a novel therapeutic strategy against cancer. Accordingly, several small-molecule inhibitors have been developed that mimic three hydrophobic groups of p53 involved in p53-MDM2 binding and thus block the p53-binding pocket on MDM2. Interestingly, presence of a fourth, solvent-exposed hydrophilic moiety in these MDM2 inhibitors is shown to enhance their binding to MDM2 by protecting the inhibitor-MDM2 binding interface from surrounding solvent. In this context, we hypothesized that vitamin folic acid (FA) may prove to be suitable as the hydrophilic cover for enhancing activity of present MDM2 inhibitors. The proposed conjugation of FA to MDM2 inhibitors may also lead to their enhanced and selective uptake by cancer cells, owing to significantly higher expression of the FA receptors on cancer cells compared to normal cells. Therefore, based on our novel hypothesis we designed FA-conjugated MDM2 inhibitors and investigated their binding with MDM2 protein as well as the FA receptor. Specifically, a molecular modeling approach combining flexible receptor docking and molecular mechanics energy minimization calculations revealed highly favorable interactions of FA-conjugated MDM2 inhibitors with both MDM2 protein and the FA receptor as compared to native crystal ligands. Furthermore, these binding interactions were found to be stable using 50,000 ps molecular dynamics simulations. In summary, the newly-designed molecules of this kind, with better MDM2 target binding and enhanced cellular uptake potential, may prove highly useful against cancer and thus warrant further experimental investigations.