标题：Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations
作者：Huang, C.; Li, Y.; Ren, H.; Wang, J.; Shao, L.; Zhang, S.; Li, G.; Yang, L.
作者机构：[Huang, C.; Li, Y.; Wang, J.; Zhang, S.] Dalian Univ Technol, Dept Mat Sci & Chem Engn, Dalian 116024, Liaoning, Peoples R China.; [Ren, H.] Shandon 更多
通讯作者地址：[Li, Y]Dalian Univ Technol, Dept Mat Sci & Chem Engn, Dalian 116024, Liaoning, Peoples R China.
来源：CURRENT MEDICINAL CHEMISTRY
关键词：Imidazoles; P38 alpha; inhibitor; 3D-QSAR; CoMFA; CoMSIA; PLS; molecular; docking; MD; lobster active conformation
摘要：P38 kinase plays a vital role in the inflammation mediated by tumor necrosis factor-alpha and interleukin-1 beta 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 p38 alpha 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-ncv(2)=0.774, R-pre(2)=0.668 and Q(2)=0.504, R-ncv(2)=0.745, R-pre(2)=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 p38 alpha 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 p38 alpha binding site. These models and the derived information may afford valuable clues for design of new potent p38 alpha inhibitors.