Structural implications of the DFD-in domain in computer-aided molecular design of MAP kinase interacting kinase 2 inhibitors

Protein translation is a key process on cell development and proliferation that is often deregulated in cancer. MAP kinase interacting kinases 1 and 2 (Mnk1/2) play a pivotal role in regulating the cap dependent translation through phosphorylation of elF4E transcription factor. Thus, Mnk1/2 targeting have been proposed as a novel therapeutic strategy that would minimize side-effects in contrast to other therapies. For this reason, there is a growing interest in designing in silico new Mnk1/2 inhibitors which demands from reliable structural models. Interestingly, the catalytic domain of Mnk proteins are characterized by a DFD motif instead of the characteristic DFG motif of other kinases. However, Mnk2 structural models described in literature are DFG mutated and do not contain the activation loop. Molecular design techniques have been applied to obtain a structural model of the full wildtype Mnk2 protein including the activation loop. The effect of the loop on the interaction mechanism of well-known ligands has been evaluated. Obtained results suggest that the presence of the activation loop is determinant for the correct prediction of the active site and it is essential for the design of new inhibitors.