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

Abstract

Mitogen-activated protein kinases-interacting kinases 1 and 2 (MNK1 and MNK2) are Ser/Thr kinases belongs to the group of Ca2+/calmodulin-dependent kinases (CaMK) that phosphorylate Eukaryotic initiation factor 4E (eIF4E) [Luc Furic.,et. al., PNAS, 2010, 107 (32):14134-14139] on Ser-209. Overexpression of eIF4E has been associated with tumoregenicity and studies have indicated that eIF4E phosphorylation is oncogenic [Jinqiang Hou. et. al., Oncotarget, 2012, 3:118-131]. Therefore, Mnk1/2 inhibitors could be effective therapeutic agents for the treatment of cancers driven by an overexpression of phosphorylated eIF4E. In the current study we have carried out molecular docking combined with molecular dynamics simulations to study the interaction between ligand and Mnk1/2 kinase catalytic domains. Three dimensional structures of both Mnk1 and Mnk2 were built using comparative modeling methods. A series of Mnk kinase inhibitors were docked to the ensemble of representative structures extracted from a clustering analysis of the MD simulations. The predicted bound conformations were further studied in explicit solvent by MD simulations. Our combined computation approach identified key residues that are important for the protein - inhibitor interactions, provides detailed understanding of the mechanism of these kinds of inhibitors and will be useful for the rational design of Mnk inhibitors.