Complex Structure Modeling of p38 MAP Kinase and Pyridyl-pyrrole Compounds

Abstract

Some pyridyl-pyrrole compounds were found to have inhibitory activities against p38 MAP kinase. Their activity was much more potent than that of SB203580 that has a similar overall structure but with a different core group, i.e., an imidazole ring. The complex structure modeling was therefore carried out in an attempt to obtain insights into the interactions of the kinase with the pyridyl-pyrrole compounds and SB203580. The resultant complex models revealed that the imidazole and the pyrrole compounds had similar binding modes and that the representative interactions between the enzyme and the ligand moiety (pyridyl or phenyl) were common. For the sulfoxy moiety including the aliphatic tethers attached to a terminal functional group, the amino acid residues interacting with the moiety were elucidated. Lastly, the affinities of the inhibitors were estimated by calculating the score values with the Ludi program and a good correlation between the p38 MAP kinase inhibitory activities and the score values was found.