Paper Title
Conformations and Validations of P38 Map Kinase Bound to Inhibitor

Abstract
P38 mitogen-activated protein (MAP) kinases signaling pathway plays an important role in inflammation. The aims of this work are to study the interaction and conformational flexibility between the p38 MAP kinase and the SB-203580 inhibitor, which is located in the ATPbinding pocket by the molecular dynamics (MD) simulations. The crystal structures of p38 MAP kinase bound to SB-203580 (pdb code 1A9U, 3MPA, 3OBG, 3GCP, 3ZS5 and 2EWA) are investigated. The six kinases exist in the DFG-in and DFG-out conformations and SB-203580 conformations share the similar binding mode. From the results, in the ATP active site, the SB-203580 forms two hydrogen bonds with the backbone NH group of Met106 and O atom of His104 in the hinge region and the NH group of Asp165 of the DFG-in loop movement. Phe166 flips out the DFG loop, which it is formed with SB-203580 by the pi-pi stacking. The SB-203580 has a stable binding with DFG-in and DFG-in mutate of P38 MAP kinase. However, it is unstable in DFG-out MAP kinase. It is also found that SB-203580 in the protein 2EWA changed conformation from DFG-in to DFG-out. The information from this study can be used to develop the new inhibitor. Keywords - P38 mitogen-activated protein (MAP) kinases; Molecular dynamics simulations (MD), DFG, SB-203580