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论文类型：期刊论文

发表时间：2014-06-01

发表刊物：CHEMICAL BIOLOGY & DRUG DESIGN

收录刊物：SCIE、PubMed、Scopus

卷号：83

期号：6

页面范围：643-655

ISSN号：1747-0277

关键字：B-Raf(V600E) kinase; Pyrazolopyrimidine- and pyrazolopyridine-based inhibitors; 3D-QSAR; docking; md

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.