Title:Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations
VOLUME: 19 ISSUE: 23
Author(s):C. Huang, Y. Li, H. Ren, J. Wang, L. Shao, S. Zhang, G. Li and L. Yang
Affiliation:Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, 116024, Liaoning, China.
Keywords:Imidazoles, P38α, inhibitor, 3D-QSAR, CoMFA, CoMSIA, PLS, molecular docking, MD, lobster active conformation
Abstract: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 threedimensional
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 Q2=0.475, R2
ncv=0.774, R2
pre=0.668 and Q2=0.504, R2
ncv=0.745, R2
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.
