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题名: 3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase
作者: Zhang, Baidong1;  Li, Yan1;  Zhang, Huixiao2;  Ai, Chunzhi3
关键词: Aurora B ;  drug design ;  3D-QSAR ;  CoMFA ;  CoMSIA ;  molecular docking ;  homology modeling
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2010-11-01
DOI: 10.3390/ijms11114326
卷: 11, 期:11, 页:4326-4347
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q(2) = 0.605, r(pred)(2) = 0.826), (q(2) = 0.52, r(pred)(2) = 0.798) and (q(2) = 0.582, r(pred)(2) = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.
关键词[WOS]: LEAST-SQUARES PLS ;  SIMILARITY INDEXES ;  ANTICANCER AGENTS ;  ANALYSIS COMSIA ;  P-GLYCOPROTEIN ;  FIELD ANALYSIS ;  SWISS-MODEL ;  POTENT ;  DISCOVERY ;  REGRESSION
语种: 英语
WOS记录号: WOS:000284575100009
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141950
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, Sch Chem Engn, Dalian 116012, Liaoning, Peoples R China
2.NW A&F Univ, Ctr Bioinformat, Yangling 712100, Shaanxi, Peoples R China
3.Chinese Acad Sci, Grad Sch, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Zhang, Baidong,Li, Yan,Zhang, Huixiao,et al. 3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2010,11(11):4326-4347.
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