Insight into the structural determinants of imidazole scaffold-based derivatives as p38 MAP kinase inhibitors by computational explorations.

P38 kinase plays a vital role in the inflammation mediated by tumor necrosis factor-α and interleukin-1β pathways, and thus the inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Presently, a combined study of three-dimensional quantitative structure-activity relationship, molecular docking and molecular dynamics (MD) was undertaken to explore the structural insights of 174 2-thioimidazole compounds influencing the p38α inhibitory activities. Both the ligand-based resultant comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models exhibited satisfactory predictability (with Q(2)=0.475, R(2)(ncv)=0.774, R(2)(pre)=0.668 and Q(2)=0.504, R(2)(ncv)=0.745, R(2)(pre)=0.709, respectively). Furthermore, good consistency was observed between the 3D-QSAR models, docking and MD results. Our findings are: i) hydrogen bonding and steric size of the molecules play crucial roles in the mechanisms of action that a medium-sized bulky substituent on the 2-position, an electropositive H-bond donor substituent on the 6-position of the pyridine ring are favorable for increasing the inhibition activity; ii) 2- Thioimidazole derivatives may bind to the p38α kinase with a "lobster" active conformation, which is fixed by four hydrogen bonds they formed with the adjacent residues (Lys53, Gly110, Met109 and Ala157) and two hydrophobic interactions (in hydrophobic pockets I and II respectively) in p38α binding site. These models and the derived information may afford valuable clues for design of new potent p38α inhibitors.