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题名: Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations
作者: Li, Yan1;  Han, Chunxiao1;  Wang, Jinghui1;  Yang, Yinfeng1;  Zhang, Jingxiao1;  Zhang, Shuwei1;  Yang, Ling2
关键词: B-Raf(V600E) kinase ;  Pyrazolopyrimidine- and pyrazolopyridine-based inhibitors ;  3D-QSAR ;  docking ;  md
刊名: CHEMICAL BIOLOGY & DRUG DESIGN
发表日期: 2014-06-01
DOI: 10.1111/cbdd.12276
卷: 83, 期:6, 页:643-655
收录类别: SCI ;  IC
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology ;  Chemistry, Medicinal
研究领域[WOS]: Biochemistry & Molecular Biology ;  Pharmacology & Pharmacy
英文摘要: Presently, both ligand-based and receptor-based 3D-QSAR modelings were performed on 107 pyrazolopyrimidine- and pyrazolopyridine-based inhibitors of B-Raf(V600E) kinase. The optimal model is successful to predict the inhibitors' activity with Q(2) of 0.504, R-ncv(2) of 0.960, and R-pred(2) of 0.872. Besides, the 3D contour maps explain well the structural requirements of the interaction between the ligand and the receptor. Furthermore, molecular docking and MD were also carried out to study the binding mode. Our findings are the following: (i) Bulky substituents at position 3, 10 and ring D improve the inhibitory activity, but impair the activity at position 5, 11, and 19. (ii) Electropositive groups at position 10, 13 and 20 and electronegative groups at position 2 increase the biological activity. (iii) Hydrophobic substituents at ring C are beneficial to improve the biological activity, while hydrophilic substituents at position 11 and ring D are good for the activity. (4) This scaffold of inhibitors may bind to the B-Raf kinase with an L' conformation and belong to type III binding mode, which is fixed by hydrophobic interaction and hydrogen bonds with residues from hinge region and DFG motif. These results may be a guidance to develop new B-Raf(V600E) kinase inhibitors.
关键词[WOS]: MOLECULAR SIMILARITY INDEXES ;  B-RAF ;  IN-SILICO ;  RAF/MEK/ERK PATHWAY ;  THERAPEUTIC TARGET ;  ANTITUMOR-ACTIVITY ;  ANALYSIS COMSIA ;  DRUG DISCOVERY ;  P-GLYCOPROTEIN ;  HUMAN CANCER
语种: 英语
WOS记录号: WOS:000336247300002
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/145505
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, Key Lab Ind Ecol & Environm Engn MOE, Dalian 116024, Liaoning, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Grad Sch, Lab Pharmaceut Resource Discovery, Dalian 116024, Liaoning, Peoples R China

Recommended Citation:
Li, Yan,Han, Chunxiao,Wang, Jinghui,et al. Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2014,83(6):643-655.
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