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Molecular Mechanism of MDM2 with Novel Small Inhibitor Recognition Explored by Molecular Dynamics Simulation and Free Energy Analysis

https://doi.org/10.14233/ajchem.2015.17382
Hui Li
School of Life Science, Liaoning University, Shenyang 110036, Liaoning Province 110036, P.R. China
Shi-Kui Hu
School of Life Science, Liaoning University, Shenyang 110036, Liaoning Province 110036, P.R. China; School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province 110016, P.R. China
Xu Wen
School of Life Science, Liaoning University, Shenyang 110036, Liaoning Province 110036, P.R. China
Xi-Hai Liang
School of Life Science, Liaoning University, Shenyang 110036, Liaoning Province 110036, P.R. China
Hong Zeng
School of Life Science, Liaoning University, Shenyang 110036, Liaoning Province 110036, P.R. China

Corresponding Author(s) : Hui Li

zhiyao77@126.com

Asian Journal of Chemistry, Vol. 27 No. 5 (2015): Vol 27 Issue 5

Abstract

P53 is a powerful anti-tumoral molecule which is frequently inactivated by its major negative regulator, MDM2. Inhibition of p52-MDM2 interaction is increasingly gaining interest in cancer therapy and drug design. Molecular docking coupled with molecular dynamics and molecular mechanics generalized. Born surface area (MM-GBSA) method was performed to investigate the binding mechanisms of compound 9c to MDM2. These results show that the van der Waals energy is the largest component of the binding free energy for the MDM2-9c complex, which is consistent with the experimental results. In addition, analysis of individual reside contribution and protein-ligand binding mode show that there are more space and opportunity for derivatization at the C-2 and C-3 position, respectively. It is expected the results obtained from this study will be valuable for future rational design of novel and potent MDM2 inhibitors targeting the p53-MDM2 interaction.

Keywords

MEM2 Molecular simulation Molecular dynamics p53
Li, H., Hu, S.-K., Wen, X., Liang, X.-H., & Zeng, H. (2015). Molecular Mechanism of MDM2 with Novel Small Inhibitor Recognition Explored by Molecular Dynamics Simulation and Free Energy Analysis. Asian Journal of Chemistry, 27(5), 1589–1592. https://doi.org/10.14233/ajchem.2015.17382
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