Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations

	Insight into the Structural Features of Pyrazolopyrimidine- and Pyrazolopyridine-based B-Raf(V600E) Kinase Inhibitors by Computational Explorations
	Li, Yan 1; Han, Chunxiao 1; Wang, Jinghui 1; Yang, Yinfeng 1; Zhang, Jingxiao 1; Zhang, Shuwei 1; Yang, Ling 2
刊名	chemical biology & drug design
	2014-06-01
卷号	83 期号:6 页码:643-655
关键词	B-Raf(V600E) kinase Pyrazolopyrimidine- and pyrazolopyridine-based inhibitors 3D-QSAR docking md
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.
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
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
收录类别	SCI ; IC
语种	英语
WOS记录号	WOS:000336247300002
公开日期	2016-05-09
内容类型	期刊论文
源URL	[http://cas-ir.dicp.ac.cn/handle/321008/145505]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
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
推荐引用方式 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.