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

Xie H, Chen L, Zhang J, Xie X, Qiu K, Fu J - Int J Mol Sci (2015)

Bottom Line: 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.The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885).This 3D QSAR approach provides significant insights that are useful for designing potent BRIs.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yunnan University, Kunming 650091, China. front701228.student@sina.com.

ABSTRACT
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 (q(2) = 0.621, r(2)(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.

No MeSH data available.


Related in: MedlinePlus

Plots of C_score values vs. biological activity (pIC50 values) of 39 inhibitors.
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ijms-16-12307-f006: Plots of C_score values vs. biological activity (pIC50 values) of 39 inhibitors.

Mentions: In order to validate the docking model in the virtual screening, the C_score values of all the 39 imidazopyridine inhibitors were assessed by using Surflex-Dock, and the correlations between the C_score values and pIC50 values of the 39 inhibitors are depicted in Figure 6. It can be shown that all the 39 inhibitors have high C_score values (C_score > 5.0), which suggests that the protomol generated by Surflex-Dock is an effective docking model in the virtual screening. In order to screen the dataset effectively, the C_score values of hit compounds were set to more than 5.0 in this study.


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

Xie H, Chen L, Zhang J, Xie X, Qiu K, Fu J - Int J Mol Sci (2015)

Plots of C_score values vs. biological activity (pIC50 values) of 39 inhibitors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490445&req=5

ijms-16-12307-f006: Plots of C_score values vs. biological activity (pIC50 values) of 39 inhibitors.
Mentions: In order to validate the docking model in the virtual screening, the C_score values of all the 39 imidazopyridine inhibitors were assessed by using Surflex-Dock, and the correlations between the C_score values and pIC50 values of the 39 inhibitors are depicted in Figure 6. It can be shown that all the 39 inhibitors have high C_score values (C_score > 5.0), which suggests that the protomol generated by Surflex-Dock is an effective docking model in the virtual screening. In order to screen the dataset effectively, the C_score values of hit compounds were set to more than 5.0 in this study.

Bottom Line: 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.The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885).This 3D QSAR approach provides significant insights that are useful for designing potent BRIs.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yunnan University, Kunming 650091, China. front701228.student@sina.com.

ABSTRACT
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 (q(2) = 0.621, r(2)(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.

No MeSH data available.


Related in: MedlinePlus