Computational studies of mitogen-activated protein kinase kinases MAP2K2, MAP2K3, and MAP2K5 for the development of selective inhibitors

Abstract

All seven human mitogen-activated protein kinase kinases (MAP2Ks) are essential for cellular processes such as cell proliferation and apoptosis, and dysfunction of MAP2Ks is associated with cancers and autoimmune diseases. 5Z-7-oxozeaenol (5Z7O) strongly inhibits MAP2K1, 2, 3, and 6, and weakly inhibits MAP2K4, 5, and 7. In this study, the potencies of 5Z7O toward MAP2K2, 3, and 5 were explored by computational methods including docking and molecular dynamics (MD) simulations using homology models. Docking simulations showed that the α, β-unsaturated ketone moiety of 5Z7O bound close to the conserved cysteine residue located in front of the DFG motif (DFG-1) in MAP2K2 and 3 as in previous studies of MAP2K1 and 6; in strong inhibition, 5Z7O binds covalently with this cysteine. MD simulations of MAP2K2 and 3 in the apo state showed that the high flexibility of a conserved “gatekeeper” methionine residue enabled access of 5Z7O to this binding site. However, in docking simulation of MAP2K5, the α, β-unsaturated ketone moiety of 5Z7O was far from the conserved DFG-1 cysteine. A threonine residue at the gatekeeper position in MAP2K5 likely prevents access of the ketone moiety to that cysteine. These findings, together with previous data, provide guidance for the development of inhibitors selective for each type of MAP2K.