Abstract
The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD) simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-π and π-π interactions, are responsible for the inhibitor associations with MDMX.
Highlights
Due to key roles in maintaining the integrity of the genome, the tumor suppressor protein p53 has been paid an extensive attention[1]
Fig 2. indicates that the root-mean-square deviations (RMSD) values of the compounds with pDI, WK23 and WW8 are higher than that of the PMI-MDMX compound, which implies that the restriction of these three inhibitor bindings on MDMX may be weaker than that of PMI
60 ns molecular dynamics simulations were performed on four inhibitor-MDMX compounds to probe the effects of inhibitor bindings on the conformational changes of MDMX
Summary
Due to key roles in maintaining the integrity of the genome, the tumor suppressor protein p53 has been paid an extensive attention[1]. The previous studies suggested that the inactivation of p53 is tightly related with human cancer, which mainly arises from either point mutations in TP53 gene or functional inhibition by negative regulators MDM2 and MDMX[4,5,6,7,8]. The data from clinical treatments proved that over-expressions of two proteins MDM2 and MDMX were found in ~50% of all cancer patients around the globe, which significantly influences the wild-type function of p53[9,10,11]. MDMX is named as MDM4 and highly homologous to MDM2. It is another significant negative regulator of p53[4, 12]. Three key residues (Phe19 ́, Trp23 ́ and Leu26 ́) can form
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