A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors

International Journal of Molecular Sciences

Huiding Xie²  Lijun Chen¹  Jianqiang Zhang²  Xiaoguang Xie²  Kaixiong Qiu¹  Jijun Fu¹ 

[1] Department of Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; E-Mails:;Department of Chemistry, Yunnan University, Kunming 650091, China; E-Mails:

关键词: imidazopyridine;    B-Raf inhibitors;    3D QSAR;    pharmacophore;    virtual screening;   

DOI  :  10.3390/ijms160612307

来源: mdpi

【 摘 要 】

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q² = 0.621, r²_pred = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.