title: Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: molecular dynamics simulation and free energy analysis.
abstract: Inhibition of the MDM2-p53 interaction is considered to be a new therapeutic strategy to activate wild-type p53 in tumors. Molecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM-GBSA) analyses were used to study the inhibitory mechanisms of four small molecule inhibitors, K23, YIN, DIZ and IMZ on the p53-MDM2 interaction. We found excellent agreement between the rank of the calculated absolute binding free energies using the MM-GBSA method and the experimentally determined rank. The results show that van der Waals energy is the dominant factor for the binding of the four inhibitors. Statistical analyses of the hydrophobic contacts between the inhibitors and MDM2 were performed, and the results suggested that these inhibitors form stable hydrophobic interactions with six residues of MDM2: Leu54, Gly58, Ile61, Met62, Val93 and His96. Calculations of the detailed van der Waals interactions between non-peptide inhibitors and individual protein residues can provide insights into the inhibitor-protein binding mechanism. Our studies suggest that the CH-π and π-π interactions between the four inhibitors and protein residues drive binding of the inhibitors in the hydrophobic cleft of MDM2.
authors.affiliation: Laboratory of Molecular Modeling and Design, State Kay Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, 116011 China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.forename: Beisi
authors.initials: B
authors.lastname: Xu
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
mesh_terms: D020816:Amino Acid Motifs; D000596:Amino Acids / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D010446:Peptide Fragments; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2