| The B-Raf kinase is a kind of tyrosine kinase receptor, which plays an important role in the ERK signal transduction pathway. The mutation of this kinase will lead to the constitutive activation of ERK pathway, which will promote the proliferation, differentiation and growth of tumor cells and consequently result in different kinds of cancers. Thus. B-Raf kinase has been regarded as an vital target in the treatment of cancer. Presently, there are only three inhibitors that got through the third phase of clinical experiment successfully and can used to inhibit B-Raf kinase in the market. However, some problems still exist, such as the weak inhibitory activity, drug resistance, side effects and so on. Therefor, it is still necessary to continue studying B-Raf kinase inhibitors with high biological activity and safety and exploring their interaction mechanism.Based on the 107 pyrazolopyrimidine and pyrazolopyridine-based inhibitors of B-Raf kinase, three-dimensional quantitative structure-activity relationship (3D-QSAR) has been applied to study the quantitative relation between these molecular structures and their biological activities. By using steric, electrostatic and hydrophobic fields, we have obtained the best 3D-QSAR model with Q2 of 0.504, R2ncv of 0.960 and R2pred of 0.872. According to the analysis of contour maps, we have estimated the effects about the introduction of substituents with different properties that can improve the inhibitors’biological activity. In addition, molecular docking and molecular dynamics have been combined together to explore the interaction mechanism between these inhibitors and B-Raf kinase. After a series of in-depth discussion, we have put forward an important result that this scaffold of inhibitors may bind to the B-Raf kinase with an "L" conformation and belong to type III binding mode. The results of our study can be a guidance not only to the modification of existing inhibitors, but also to the synthesis of new potent B-Raf kinase inhibitors. |
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