The p53 is one of the most important tumor suppressor proteins that control cell cycle arrest, DNA repair and apoptosis. The most studied negative regulator of p53 is E3-ligase HDM2 (MDM2). Our work involves development of an effective inhibitor of the MDM2-p53 interaction, but it is well-known that high target activity is not enough and drug must be able to penetrate barriers of the organism to reach the target (in case of brain disorders it is not only GI tract but also BBB).
Our group use both in silico (advanced protein-ligand docking) and in vitro (high-content screening and PAMPA) methods to analyze a role of active functional groups that can improve membrane permeability (such as lipophilic amino acids or framework structures) of initial compounds.
We found that modification of MDM2 inhibitors structure with membranotropic fragments not only increases ability of the molecule to penetrate membranes without losing solubility compared to the starting material, but their inhibitory effect exceeds the ability of the original inhibitors.
These compounds will be further modified to improve both the permeability and the target activity and check in vivo.