Mitogen-activated protein kinase-interacting kinases (Mnk1 and Mnk2) are emerging and attractive anticancer targets. Mnks possess unique structural features, elevating their appeal for structure-based targeted-inhibitor discovery. Nonetheless, the lack of proper structural platforms obstructs the development of selective Mnk inhibitors. We have used available crystallographic data to create complete homology models of Mnk1 and Mnk2, in their inactive states. Then, all-atom accelerated molecular dynamics were used to demonstrate that their activation by phosphorylation grants access to distinct activation loop conformations, steering the inactive-to-active conformational transformation. Our simulations suggest that the dynamics of the activation differ between Mnk1 and Mnk2, despite the high structural similarity between them. Finally, we have used the active state Mnk2 models to successfully elucidate several ambiguous binding trends of in-house Mnk inhibitors, as indicated by kinase assays. These outcomes provide critical atomistic-level insights of the Mnk activation process, while creating valuable platforms to enable the structure-based design of Mnk-inhibitors that may develop into future anticancer agents.

Computational modeling of the conformational dynamics of the activation process of MAPK-interacting kinases (Mnks)

251st National Meeting (2016)

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