Type II inhibitor Doramapimod can bind to human p38α MAP Kinase even in the DFG-in state

What is it about?

The type II MAP Kinase inhibitors were thought to bind to a so-called allosteric pocket which is revealed only in the “out” state of the DFG motif (i.e., Asp168-Phe169-Gly170) of the activation loop. In this study we have shown for the first time that the type II inhibitor Doramapimod (BIRB-796) can initially bind to human p38α MAP Kinase in the DFG-in state of its activation loop in a new, previously unseen configuration, what is followed on a microsecond time-scale by a switch in the substrate binding mode which finally improves accommodation of the inhibitor. Molecular modelling has confirmed that Doramapimod combines the features of type I and II inhibitors of p38α MAPK, i.e., can directly and indirectly compete with the binding of the ATP cofactor.

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Why is it important?

MAPK is known to play an important role in inflammation, cell proliferation and differentiation, apoptosis and invasion, and its malfunction is associated with a wide range of pathological conditions, making it an important target for drug discovery. We have shown that both DFG-in and DFG-out states are involved in the binding of Doramapimod (BIRB-796) and other Urea-Based type II inhibitors of MAPK. Thus, optimization of the initial binding in the DFG-in state and the final accommodation in the DFG-out state should be both considered at designing novel efficient type II inhibitors of MAPK and homologous proteins.

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