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学科主题: 物理化学
题名: A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors
作者: Hao, Ming1;  Ren, Hong2, 3;  Luo, Fang4;  Zhang, Shuwei1;  Qiu, Jieshan1;  Ji, Mingjuan4;  Si, Hongzong5, 6;  Li, Guohui3
通讯作者: QiuJieshan ;  李国辉
关键词: 3D-QSAR ;  molecular dynamics ;  MK-2 inhibitors ;  CoMFA ;  CoMSIA
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2012-06-01
DOI: 10.3390/ijms13067057
卷: 13, 期:6, 页:7057-7079
收录类别: SCI
文章类型: Article
部门归属: 11
项目归属: 1106
产权排名: 3,2
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: Mitogen-activated protein kinase-activated protein kinase 2 (MK-2) has been identified as a drug target for the treatment of inflammatory diseases. Currently, a series of thiourea analogs as potent MK-2 inhibitors were studied using comprehensive computational methods by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in activities. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r(ncv)(2), q(2) values of 0.974, 0.536 for the internal validation, and r(pred)(2), r(m)(2) values of 0.910, 0.723 for the external validation and Roy's index, respectively. In addition, more rigorous validation criteria suggested by Tropsha were also employed to check the built models. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules: (i) The substituent with a bulky size and electron-rich group at the C5 position of the pyrazine ring is required to enhance the potency; (ii) The H-bond acceptor group in the C3 position of the pyrazine ring is likely to be helpful to increase MK-2 inhibition; (iii) The small and electropositive substituent as a hydrogen bond donor of the C2 position in the oxazolone ring is favored; In addition, several important amino acid residues were also identified as playing an important role in MK-2 inhibition. The agreement between 3D-QSAR, molecular docking and molecular dynamics simulations also proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential MK-2 inhibitors.
关键词[WOS]: ACTIVATED PROTEIN-KINASE-2 MK-2 ;  PROTEIN-KINASE 2 ;  ALPHA CONVERTING-ENZYME ;  MK2 INHIBITORS ;  BENZOTHIOPHENE INHIBITORS ;  MOLECULAR-DYNAMICS ;  TIBO DERIVATIVES ;  QSAR MODELS ;  SELECTIVITY ;  REGRESSION
语种: 英语
WOS记录号: WOS:000306188700032
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/117984
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 116023, 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 Dynam, Lab Mol Modeling & Design, Dalian 116023, Peoples R China
4.Chinese Acad Sci, Grad Sch, Coll Chem & Chem Engn, Beijing 100049, Peoples R China
5.Qingdao Univ, Inst Computat Sci & Engn, Lab New Fibrous Mat & Modern Text, Growing Base State Key Lab, Qingdao 266071, Peoples R China
6.Lanzhou Univ, Dept Chem, Lanzhou 730000, Peoples R China

Recommended Citation:
Hao, Ming,Ren, Hong,Luo, Fang,et al. A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2012,13(6):7057-7079.
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