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题名: Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations
作者: Huang, C.1;  Li, Y.1;  Ren, H.2, 3;  Wang, J.1;  Shao, L.4;  Zhang, S.1;  Li, G.3;  Yang, L.5
关键词: Imidazoles ;  P38 alpha ;  inhibitor ;  3D-QSAR ;  CoMFA ;  CoMSIA ;  PLS ;  molecular docking ;  MD ;  lobster active conformation
刊名: CURRENT MEDICINAL CHEMISTRY
发表日期: 2012-08-01
卷: 19, 期:23, 页:4024-4037
收录类别: SCI
文章类型: Review
类目[WOS]: Biochemistry & Molecular Biology ;  Chemistry, Medicinal ;  Pharmacology & Pharmacy
研究领域[WOS]: Biochemistry & Molecular Biology ;  Pharmacology & Pharmacy
英文摘要: 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.
关键词[WOS]: ACTIVATED PROTEIN-KINASE ;  FIELD ANALYSIS COMFA ;  MOLECULAR DOCKING ;  BIOLOGICAL EVALUATION ;  QUANTITATIVE STRUCTURE ;  COMBINED 3D-QSAR ;  3D QSAR ;  DESIGN ;  PATHWAY ;  POTENT
语种: 英语
WOS记录号: WOS:000307848800017
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142937
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Dalian Univ Technol, Dept Mat Sci & Chem Engn, Dalian 116024, Liaoning, Peoples R China
2.Shandong Univ, Sch Med, Qi Lu Hosp, Dept Ophthalmol, Jinan 250012, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React, Lab Mol Modeling & Design, Dalian 116023, Peoples R China
4.Shijiazhuang Tiedao Univ, Sifang Coll, Shijiazhuang 051132, Hebei, Peoples R China
5.Chinese Acad Sci, Grad Sch, Lab Pharmaceut Resource Discovery, Dalian Inst Chem Phys, Dalian 116023, Peoples R China

Recommended Citation:
Huang, C.,Li, Y.,Ren, H.,et al. Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations[J]. CURRENT MEDICINAL CHEMISTRY,2012,19(23):4024-4037.
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