Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods

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.

In Silico Approach in the Evaluation of Pro-Inflammatory Potential of Polycyclic Aromatic Hydrocarbons and Volatile Organic Compounds through Binding Affinity to the Human Toll-Like Receptor 4

“…Figure 10 K demonstrates a noticeable difference near residue 101. These differences in RMSF values could be due to changes in internal dynamics and interaction intensities [ 40 ]. Overall, minimal fluctuations were observed once the ligand binds to the receptor.…”

Recent Developments and Applications of the MMPBSA Method

“…There are many applications of MMPBSA that involve the calculation of protein-protein or protein-peptide binding affinities. For anti-cancer applications, we saw studies on complexes of an ankyrin repeat with integrin-linked kinase binding to PINCH1 (Gautam et al, 2014 , 2015 ), cyclin-dependent kinase 8 with cyclin C (Xu et al, 2014 ), Hsp90 with Cdc37-derived peptides (Wang L. et al, 2015 ), and p53 with MDMX (Shi et al, 2015 ). As an illustration, Wang et al designed an eleven-residue peptide that was able to bind to Hsp90 with a predicted affinity of 6.9 mM, which was comparable to the experimental value of 3.0 mM (Wang L. et al, 2015 ).…”

Numerical Calculation of Energy Between the Sealing Materials and Sepiolite Crystal on the Different Directions

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