Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations

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• 作者：Srinivasaraghavan Kannan ; Anders Poulsen ; Hai Yan Yang ; Melvyn Ho ; Shi Hua Ang ; Tan Sum Wai Eldwin ; Duraiswamy Athisayamani Jeyaraj ; Lohitha Rao Chennamaneni ; Boping Liu ; Jeffrey Hill ; Chandra S. Verma ; Kassoum Nacro
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：January 13, 2015
• 年：2015
• 卷：54
• 期：1
• 页码：32-46
• 全文大小：818K
• ISSN：1520-4995

文摘

Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potential therapeutic targets for cancer. Recently, we have designed and synthesized a series of novel imidazopyridine and imidazopyrazine derivatives that inhibit Mnk1/2 kinases with a potency in the nanomolar to micromolar range. In the current work we model the inhibition of Mnk kinase activity by these inhibitors using various computational approaches. Combining homology modeling, docking, molecular dynamics simulations, and free energy calculations, we find that all compounds bind similarly to the active sites of both kinases with their imidazopyridine and imidazopyrazine cores anchored to the hinge regions of the kinases through hydrogen bonds. In addition, hydrogen bond interactions between the inhibitors and the catalytic Lys78 (Mnk1), Lys113 (Mnk2) and Ser131 (Mnk1), Ser166 (Mnk2) appear to be important for the potency and stability of the bound conformations of the inhibitors. The computed binding free energies (螖G_Pred) of these inhibitors are in accord with experimental bioactivity data (pIC₅₀) with correlation coefficients (r²) of 0.70 and 0.68 for Mnk1 and Mnk2 respectively. van der Waals energies and entropic effects appear to dominate the binding free energy (螖G_Pred) for each Mnk鈥搃nhibitor complex studied. The models suggest that the activities of these small molecule inhibitors arise from interactions with multiple residues in the active sites, particularly with the hydrophobic residues.