Tracking binding modes of 1,2,4-trisubstituted imidazolinone P38 MAP kinase and ERK-2 inhibitors.

Putative binding modes of recently reported p38 MAP Kinase and ERK-2 inhibitors containing 1,2,4-tri-substituted imidazolinone have been investigated using molecular docking methods In the case of p38 MAP Kinase, X-ray structures with both DFG-in and DFG-out conformations of the activation loop have been employed for docking studies. The present investigations demonstrate that the DFG-out conformation of the activation loop in p38 MAP Kinase accommodates the 1,2,4-tri-substituted imidazolinones with greater computed binding affinities than the alternative DFG-in conformation. The best scoring binding modes in ERK-2 are distinctly different from those found in the p38 MAP Kinase structures. Both sets of binding modes are characterized by an extensive network of hydrophobic and π-cation interactions, with the hinge region showing little hydrogen bonding propensity with the top-ranked poses. Thus, these docking studies provide a putative pathway for lead optimizations in which hydrogen bonding interactions with the hinge region residues are feasible.