A COMPUTATIONAL STUDY ON INTERACTIONS OF SMALL-MOLECULE AND PEPTIDE-BASED MDM2 INHIBITORS

Abstract

THIS THESIS WAS FOCUSING ON BETTER UNDERSTANDING THE INTERACTIONS OF SMALL-MOLECULE AND PEPTIDE-BASED MDM2 INHIBITORS, ESPECIALLY HYDROGEN BOND, HALOGEN BOND, AND AROMATIC INTERACTIONS. FROM THE DOCKING AND MOLECULAR DYNAMICS SIMULATION ANALYSIS, BESIDES HYDROGEN BONDS, CHLORO-PHENYL GROUP IS IMPORTANT FOR EFFECTIVE MDM2 INHIBITORS, IN WHICH THE CHLORINE ATOM CONTRIBUTES TO BINDING AFFINITY BY FORMATION OF HALOGEN BOND OR HYDROPHOBIC CAVITY-FILLING EFFECT, WHILE THE PHENYL RING CONTRIBUTES AROMATIC INTERACTION TO IMPROVE BINDING AFFINITY OF BOTH SMALL-MOLECULE AND PEPTIDE-BASED MDM2 INHIBITORS. IN ADDITION, MOLECULAR DYNAMICS SIMULATIONS WERE CARRIED OUT TO CALCULATE THE ACCURATE BINDING FREE ENERGY AND ENERGETIC CONTRIBUTION OF SINGLE RESIDUE. FURTHERMORE, OPTIMIZED SMALL-MOLECULE AND PEPTIDE-BASED MDM2 INHIBITORS WERE DESIGNED AND EVALUATED TO HAVE IMPROVED BINDING AFFINITIES.