title: Insight into the structural features of pyrazolopyrimidine- and pyrazolopyridine-based B-Raf(V600E) kinase inhibitors by computational explorations.
abstract: 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(2) ncv of 0.960, and R(2) pred 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.
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116024, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Han
authors.forename: Jinghui
authors.initials: J
authors.lastname: Wang
authors.forename: Yinfeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Jingxiao
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D048493:Proto-Oncogene Proteins B-raf
keywords: 3D-QSAR; B-RafV600E kinase; Pyrazolopyrimidine- and pyrazolopyridine-based inhibitors; docking; md