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 (Δ<i>G</i><sub>Pred</sub>) of these
inhibitors are in accord with experimental bioactivity data (pIC<sub>50</sub>) with correlation coefficients (<i>r</i><sup>2</sup>) 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 (Δ<i>G</i><sub>Pred</sub>) for each Mnk–inhibitor
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
