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Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation

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Abstract

Trametinib was endorsed by the FDA in 2013 as a single agent for adult melanoma patients. Trametinib inhibits cell growth and proliferation in multiple tumor xenografts by preventing RAF phosphorylation of MEK and thus restricting accumulation of activated MEK. In this study, the focus of investigation was the mechanism of the interaction between trametinib and MEK1/2 via computational simulation. To specify the best interaction site of inhibitor with MEK1/2 based on the interaction energy ranking, first we performed a docking and then we studied the interactions of the ATP-bound MEK with trametinib, with RAF and the complex of the ATP-bound MEK–trametinib with RAF via molecular dynamic simulations. The results showed that trametinib inactivates the enzyme by bonding to a group of amino acids including Lys97/101, SER218/216, Asp208/212, and Met143/147 in MEK1/2. By bonding to the essential amino acids, trametinib inhibits the activity of the enzyme. All in all, the acquired results can be of great use in designing new inhibitors.

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Acknowledgements

This study is related to the project NO. 1397/44135 From Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran. We also appreciate the “Student Research Committee” and “Research & Technology Chancellor” in Shahid Beheshti University of Medical Sciences for their financial support of this study.

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Authors and Affiliations

  1. Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sh. Hashemzadeh

  2. Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sh. Hashemzadeh & H. Rafii-Tabar

  3. Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    F. Ramezani

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  1. Sh. Hashemzadeh
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  2. F. Ramezani
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  3. H. Rafii-Tabar
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Correspondence to F. Ramezani or H. Rafii-Tabar.

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Hashemzadeh, S., Ramezani, F. & Rafii-Tabar, H. Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation. Interdiscip Sci Comput Life Sci 11, 115–124 (2019). https://doi.org/10.1007/s12539-018-0305-4

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  • DOI: https://doi.org/10.1007/s12539-018-0305-4

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