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Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations
Li, Yan1; Han, Chunxiao1; Wang, Jinghui1; Yang, Yinfeng1; Zhang, Jingxiao1; Zhang, Shuwei1; Yang, Ling2
KeywordB-raf(V600e) Kinase Pyrazolopyrimidine- And Pyrazolopyridine-based Inhibitors 3d-qsar Docking Md
Source PublicationCHEMICAL BIOLOGY & DRUG DESIGN
2014-06-01
DOI10.1111/cbdd.12276
Volume83Issue:6Pages:643-655
Indexed BySCI ; IC
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Medicinal
WOS Research AreaBiochemistry & Molecular Biology ; Pharmacology & Pharmacy
WOS KeywordMOLECULAR SIMILARITY INDEXES ; B-RAF ; IN-SILICO ; RAF/MEK/ERK PATHWAY ; THERAPEUTIC TARGET ; ANTITUMOR-ACTIVITY ; ANALYSIS COMSIA ; DRUG DISCOVERY ; P-GLYCOPROTEIN ; HUMAN CANCER
AbstractPresently, 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.
Language英语
WOS IDWOS:000336247300002
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/321008/145505
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Li, Yan.,Han, Chunxiao.,Wang, Jinghui.,Yang, Yinfeng.,Zhang, Jingxiao.,...&Yang, Ling.(2014).Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations.CHEMICAL BIOLOGY & DRUG DESIGN,83(6),643-655.
MLA Li, Yan,et al."Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations".CHEMICAL BIOLOGY & DRUG DESIGN 83.6(2014):643-655.
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