Virtual Screening for Type ⅡB Inhibitors of B-RafV600E Kinase

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Author(s): Kai-Xiong Qiu, Wen Zhang, Fang Yu, Wei Li, Zhong-Wen Sun, Shu-Qun Zhang, Ya-Juan Chen, Hui-Ding Xie*.

Journal Name: Current Computer-Aided Drug Design

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Background: B-RafV600E kinase was identified as an important target in current cancer treatment, and the type ⅡB inhibitors show good qualities in preclinical studies. Therefore, it is very important to discover novel ⅡB inhibitors of B-RafV600E kinase.

Methods: In order to discover novel ⅡB inhibitors of B-RafV600E kinase, a virtual screening against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔGbind) calculation studies. The inhibitory activities against A375 cell lines of the hit compounds were tested by using MTT assay.

Results: Five promising hit compounds were obtained after the screening, and all the five hit compounds show good inhibitory rates against A375 cell lines.

Conclusion: The combined approach of the virtual screening in our work is effective, which can be used to discover novel inhibitors with new skeleton. In addition, the five compounds obtained from the screening show good inhibitory rates against A375 cell lines, which can be taken to develop new ⅡB inhibitors of B-RafV600E kinase.

Keywords: B-RafV600E Kinase; Type ⅡB Inhibitors; Virtual Screening; Pharmacophore Modelling; Molecular Docking; 3D-QSAR; Binding Free Energy Calculation

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(E-pub Ahead of Print)
DOI: 10.2174/1573409915666190130162821
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