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.