Molecular modeling of p38α mitogen-activated protein kinase inhibitors through 3D-QSAR and molecular dynamics simulations.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in inflammation and other physiological processes. Because specific inhibitors of p38α and p38β MAPK block the production of the major inflammatory cytokines and other proteins, p38α and p38β MAPK represent promising targets for the treatment of inflammation. In this work, a series of p38α inhibitors based on the structural scaffold of 4-benzoyl-5-aminopyrazole were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for p38 MAPK inhibition. Furthermore, we employed molecular dynamics (MD) simulations and the MM/GBSA method to compare the binding modes and binding free energies of a potent and selective compound interacting with p38α, p38β, p38γ, and p38δ MAPK in detail. Contour maps generated via 3D-QSAR analysis identified several key interactions that were also indicated through MD simulations. The binding free energies calculated via the MM/GBSA method were strongly correlated with experimentally observed biological activities and explained the selective inhibition of p38α and p38β, but not p38γ and p38δ detected here. On the basis of the obtained results, we provide insights regarding the development of novel potent p38α MAPK inhibitors.