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.

中文翻译：

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用对接和分子动力学模拟研究MEK1 / 2与曲美替尼相互作用的分子机理。

曲美替尼在2013年被FDA批准为成人黑色素瘤患者的单一药物。曲美替尼通过阻止RAF磷酸化MEK从而抑制多种肿瘤异种移植物中的细胞生长和增殖，从而限制了活化MEK的积累。在这项研究中，研究的重点是通过计算模拟使曲美替尼与MEK1 / 2相互作用的机理。为了根据相互作用能排名确定抑制剂与MEK1 / 2的最佳相互作用位点，首先进行了对接，然后研究了ATP结合的MEK与曲美替尼，RAF和ATP结合的MEK的配合物之间的相互作用。 -trametinib与RAF的分子动力学模拟。结果表明曲美替尼通过与Lys97 / 101，SER218 / 216，Asp208 / 212，和MEK1 / 2中的Met143 / 147。通过与必需氨基酸结合，曲美替尼抑制了酶的活性。总而言之，所获得的结果可以在设计新的抑制剂中有很大的用途。