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题名: Insight into the Structural Requirements of Benzimidazole Derivatives as Interleukin-2 Inducible T-cell Kinase Inhibitors by Computational Explorations
作者: Wang, Jinghui1;  Li, Feng1, 2;  Li, Yan;  Yang, Yinfeng1;  Wang, Bin3;  Zhang, Shuwei1;  Yang, Ling4
关键词: 3D-QSAR ;  ITK inhibitors ;  comparative molecular field analysis ;  comparative molecular similarity indices analysis ;  molecular dynamics ;  docking
刊名: INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
发表日期: 2013-11-05
DOI: 10.1002/qua.24470
卷: 113, 期:21, 页:2385-2396
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Physical ;  Mathematics, Interdisciplinary Applications ;  Physics, Atomic, Molecular & Chemical
研究领域[WOS]: Chemistry ;  Mathematics ;  Physics
英文摘要: In the present work, a set of ligand- and receptor-based 3D-QSAR models were developed to explore the structure-activity relationship of 109 benzimidazole-based interleukin-2-inducible T-cell kinase (ITK) inhibitors. In order to reveal the requisite 3D structural features impacting the biological activities, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking, and molecular dynamics were applied. The results showed that the ligand-based CoMFA model (Q(2) = 0.552, R-ncv(2) = 0.908, R-pred(2) = 0.787, SEE = 0.252, SEP = 0.558) and CoMSIA model (Q(2) = 0.579, R-ncv(2) = 0.914, R-pred(2) = 0.893, SEE = 0.240, SEP = 0.538) were superior to other models with greater predictive power. In addition, a combined analysis between the 3D contour maps and docking results showed that: (1) Compounds with bulky or hydrophobic substituents near ring D and electropositive or hydrogen acceptor groups around rings C and D could increase the activity. (2) The key amino acids impacting the receptor-ligand interactions in the binding pocket are Met438, Asp500, Lys391, and Glu439. The results obtained from this work may provide helpful guidelines in design of novel benzimidazole analogs as inhibitors of ITK. (c) 2013 Wiley Periodicals, Inc.
关键词[WOS]: MOLECULAR SIMILARITY INDEXES ;  ITK INHIBITORS ;  DRUG DESIGN ;  SIGNAL-TRANSDUCTION ;  CRYSTAL-STRUCTURES ;  CROSS-VALIDATION ;  TYROSINE KINASE ;  ANALYSIS COMSIA ;  FIELD ANALYSIS ;  3D QSAR
语种: 英语
WOS记录号: WOS:000325078500008
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137901
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, Liaoning, Peoples R China
2.Henan Inst Engn, Dept Civil Engn, Zhengzhou 451191, Henan, Peoples R China
3.Dalian Ocean Univ, Aquat Prod Life Acad, Dalian 116023, Liaoning, Peoples R China
4.Chinese Acad Sci, Lab Pharmaceut Resource Discovery, Dalian Inst Chem Phys, Grad Sch, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Wang, Jinghui,Li, Feng,Li, Yan,et al. Insight into the Structural Requirements of Benzimidazole Derivatives as Interleukin-2 Inducible T-cell Kinase Inhibitors by Computational Explorations[J]. INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY,2013,113(21):2385-2396.
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