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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 QFIT values vs. biological activity (pIC50 values) of 39 inhibitors.
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ijms-16-12307-f005: Plots of QFIT values vs. biological activity (pIC50 values) of 39 inhibitors.

Mentions: In order to validate the pharmacophore model in the virtual screening, the QFIT (pharmacophoric match between query and the hit compound) values of all the 39 imidazopyridine inhibitors were tested by using the obtained best pharmacophore model (Model_06), and the correlations between the QFIT values and pIC50 values of the 39 inhibitors are depicted in Figure 5. It can be seen that 37 of 39 inhibitors have high QFIT values (QFIT > 45), which indicates that the Model_06 is a potent pharmacophore model in the virtual screening. In order to screen the dataset effectively, the QFIT values of hit compounds were set to more than 45 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 QFIT 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-f005: Plots of QFIT values vs. biological activity (pIC50 values) of 39 inhibitors.
Mentions: In order to validate the pharmacophore model in the virtual screening, the QFIT (pharmacophoric match between query and the hit compound) values of all the 39 imidazopyridine inhibitors were tested by using the obtained best pharmacophore model (Model_06), and the correlations between the QFIT values and pIC50 values of the 39 inhibitors are depicted in Figure 5. It can be seen that 37 of 39 inhibitors have high QFIT values (QFIT > 45), which indicates that the Model_06 is a potent pharmacophore model in the virtual screening. In order to screen the dataset effectively, the QFIT values of hit compounds were set to more than 45 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