DICP OpenIR
Subject Area物理化学
A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors
Hao, Ming1; Ren, Hong2,3; Luo, Fang4; Zhang, Shuwei1; Qiu, Jieshan1; Ji, Mingjuan4; Si, Hongzong5,6; Li, Guohui3; QiuJieshan; Li GH(李国辉)
Keyword3d-qsar Molecular Dynamics Mk-2 Inhibitors Comfa Comsia
Source PublicationINTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
2012-06-01
ISSN1661-6596
DOI10.3390/ijms13067057
Volume13Issue:6Pages:7057-7079
Indexed BySCI
SubtypeArticle
Department11
Funding Project1106
Contribution Rank3,2
WOS HeadingsScience & Technology ; Physical Sciences
WOS SubjectChemistry, Multidisciplinary
WOS Research AreaChemistry
WOS KeywordACTIVATED PROTEIN-KINASE-2 MK-2 ; PROTEIN-KINASE 2 ; ALPHA CONVERTING-ENZYME ; MK2 INHIBITORS ; BENZOTHIOPHENE INHIBITORS ; MOLECULAR-DYNAMICS ; TIBO DERIVATIVES ; QSAR MODELS ; SELECTIVITY ; REGRESSION
AbstractMitogen-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.
Language英语
WOS IDWOS:000306188700032
Citation statistics
Cited Times:3[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/117984
Collection中国科学院大连化学物理研究所
Corresponding AuthorQiuJieshan; Li GH(李国辉)
Affiliation1.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
GB/T 7714
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.
APA Hao, Ming.,Ren, Hong.,Luo, Fang.,Zhang, Shuwei.,Qiu, Jieshan.,...&李国辉.(2012).A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,13(6),7057-7079.
MLA Hao, Ming,et al."A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 13.6(2012):7057-7079.
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