Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations
文献类型：期刊论文
| 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 |
| 刊名 | current medicinal chemistry
 |
| 出版日期 | 2012-08-01 |
| 卷号 | 19期号:23页码:4024-4037 |
| 关键词 | Imidazoles P38 alpha inhibitor 3D-QSAR CoMFA CoMSIA PLS molecular docking MD lobster active conformation |
| 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. |
| 类目[WOS] | biochemistry & molecular biology ; chemistry, medicinal ; pharmacology & pharmacy |
| 研究领域[WOS] | biochemistry & molecular biology ; pharmacology & pharmacy |
| 关键词[WOS] | activated protein-kinase ; field analysis comfa ; molecular docking ; biological evaluation ; quantitative structure ; combined 3d-qsar ; 3d qsar ; design ; pathway ; potent |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000307848800017 |
| 公开日期 | 2015-11-17 |
| 源URL | [http://159.226.238.44/handle/321008/142937]  |
| 专题 | 大连化学物理研究所_中国科学院大连化学物理研究所 |
| 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 |
| 推荐引用方式 GB/T 7714 | 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. |
| APA | Huang, C..,Li, Y..,Ren, H..,Wang, J..,Shao, L..,...&Yang, L..(2012).Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations.current medicinal chemistry,19(23),4024-4037. |
| MLA | Huang, C.,et al."Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations".current medicinal chemistry 19.23(2012):4024-4037. |
入库方式： OAI收割
来源：大连化学物理研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。