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:Li, Y
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
出版年:2012
卷:19
期:23
页码:4024-4037
DOI:10.2174/092986712802002608
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.
收录类别:SCOPUS;SCIE
WOS核心被引频次:7
Scopus被引频次:7
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-84865714836&doi=10.2174%2f092986712802002608&partnerID=40&md5=ebff1d6627259577b67d9be98433024d
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