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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

The selected GALAHAD model includes two acceptor atoms (green), three donor atoms (magenta) and three hydrophobes (cyan). The sphere sizes indicate query tolerances.
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ijms-16-12307-f001: The selected GALAHAD model includes two acceptor atoms (green), three donor atoms (magenta) and three hydrophobes (cyan). The sphere sizes indicate query tolerances.

Mentions: After the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) run, twenty pharmacophore models were generated with default parameters, for which statistical values are listed in Table 2. Among the conflicting demands of maximizing pharmacophore consensus, maximizing steric consensus, and minimizing energy, each obtained model represents a different tradeoff. As shown in Table 2, each model has Pareto rank 0, which implies no one model is superior to any other one. Model_12 has a high energy, which is due to steric clashes [24]. The good models should have small value of energy, high values of Specificity, N_hits, Sterics, H-bond and Mol_Qry [25]. Therefore, Model_06 was considered to be the best model and its statistical values are listed in Table 2. This model was not only used for the molecular alignment to produce CoMFA and CoMSIA models in the 3D QSAR studies, but also was converted into a UNITY query for virtual screening studies. As shown in Figure 1, this model contains two acceptor atoms, three donor atoms and three hydrophobes, and the nitrogen atom attached to –SO2– group acts both acceptor and donor atoms.


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)

The selected GALAHAD model includes two acceptor atoms (green), three donor atoms (magenta) and three hydrophobes (cyan). The sphere sizes indicate query tolerances.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-12307-f001: The selected GALAHAD model includes two acceptor atoms (green), three donor atoms (magenta) and three hydrophobes (cyan). The sphere sizes indicate query tolerances.
Mentions: After the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) run, twenty pharmacophore models were generated with default parameters, for which statistical values are listed in Table 2. Among the conflicting demands of maximizing pharmacophore consensus, maximizing steric consensus, and minimizing energy, each obtained model represents a different tradeoff. As shown in Table 2, each model has Pareto rank 0, which implies no one model is superior to any other one. Model_12 has a high energy, which is due to steric clashes [24]. The good models should have small value of energy, high values of Specificity, N_hits, Sterics, H-bond and Mol_Qry [25]. Therefore, Model_06 was considered to be the best model and its statistical values are listed in Table 2. This model was not only used for the molecular alignment to produce CoMFA and CoMSIA models in the 3D QSAR studies, but also was converted into a UNITY query for virtual screening studies. As shown in Figure 1, this model contains two acceptor atoms, three donor atoms and three hydrophobes, and the nitrogen atom attached to –SO2– group acts both acceptor and donor atoms.

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