Limits...
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

(a) Steric contour maps in combination with compounds 18 and 10: green contours refer to sterically favored regions; yellow contours indicate sterically disfavored areas; (b) Electrostatic contour maps in combination with compound 18: blue contours refer to regions where positively charged substituents are favored; red contours indicate regions where negatively charged substituents are favored; (c) Hydrophobic contour maps in combination with compounds 18 and 10: yellow contours indicate regions where hydrophobic substituents are favored; white contours refer to regions where hydrophilic substituents are favored; (d) HBD contour map in combination with compound 18: cyan contours indicate HBD substituents in this region are favorable to activity; purple contours represent that HBD groups in this area are unfavorable; and (e) HBA contour maps in combination with compound 18: magenta contours show regions where HBA substituents are expected; red contours refer to areas where HBA substituents are unexpected.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4490445&req=5

ijms-16-12307-f004: (a) Steric contour maps in combination with compounds 18 and 10: green contours refer to sterically favored regions; yellow contours indicate sterically disfavored areas; (b) Electrostatic contour maps in combination with compound 18: blue contours refer to regions where positively charged substituents are favored; red contours indicate regions where negatively charged substituents are favored; (c) Hydrophobic contour maps in combination with compounds 18 and 10: yellow contours indicate regions where hydrophobic substituents are favored; white contours refer to regions where hydrophilic substituents are favored; (d) HBD contour map in combination with compound 18: cyan contours indicate HBD substituents in this region are favorable to activity; purple contours represent that HBD groups in this area are unfavorable; and (e) HBA contour maps in combination with compound 18: magenta contours show regions where HBA substituents are expected; red contours refer to areas where HBA substituents are unexpected.

Mentions: CoMSIA not only calculates steric and electrostatic fields as in CoMFA, but also additionally computes hydrophobic, HBD and HBA fields. The CoMSIA contour maps of steric, electrostatic, hydrophobic, HBD, and HBA fields are revealed in Figure 4a–e. Compound 18 and compound 10 were selected to be superimposed into the contour maps because compound 18 is the most active compound in all 39 imidazopyridines and compound 10 is the least active compound in 30 compounds (compounds 4–33) in which there is a substituent group attached to the imidazole ring. For each field, the favorable and disfavored contours represent 80% and 20% level contributions, respectively.


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)

(a) Steric contour maps in combination with compounds 18 and 10: green contours refer to sterically favored regions; yellow contours indicate sterically disfavored areas; (b) Electrostatic contour maps in combination with compound 18: blue contours refer to regions where positively charged substituents are favored; red contours indicate regions where negatively charged substituents are favored; (c) Hydrophobic contour maps in combination with compounds 18 and 10: yellow contours indicate regions where hydrophobic substituents are favored; white contours refer to regions where hydrophilic substituents are favored; (d) HBD contour map in combination with compound 18: cyan contours indicate HBD substituents in this region are favorable to activity; purple contours represent that HBD groups in this area are unfavorable; and (e) HBA contour maps in combination with compound 18: magenta contours show regions where HBA substituents are expected; red contours refer to areas where HBA substituents are unexpected.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-12307-f004: (a) Steric contour maps in combination with compounds 18 and 10: green contours refer to sterically favored regions; yellow contours indicate sterically disfavored areas; (b) Electrostatic contour maps in combination with compound 18: blue contours refer to regions where positively charged substituents are favored; red contours indicate regions where negatively charged substituents are favored; (c) Hydrophobic contour maps in combination with compounds 18 and 10: yellow contours indicate regions where hydrophobic substituents are favored; white contours refer to regions where hydrophilic substituents are favored; (d) HBD contour map in combination with compound 18: cyan contours indicate HBD substituents in this region are favorable to activity; purple contours represent that HBD groups in this area are unfavorable; and (e) HBA contour maps in combination with compound 18: magenta contours show regions where HBA substituents are expected; red contours refer to areas where HBA substituents are unexpected.
Mentions: CoMSIA not only calculates steric and electrostatic fields as in CoMFA, but also additionally computes hydrophobic, HBD and HBA fields. The CoMSIA contour maps of steric, electrostatic, hydrophobic, HBD, and HBA fields are revealed in Figure 4a–e. Compound 18 and compound 10 were selected to be superimposed into the contour maps because compound 18 is the most active compound in all 39 imidazopyridines and compound 10 is the least active compound in 30 compounds (compounds 4–33) in which there is a substituent group attached to the imidazole ring. For each field, the favorable and disfavored contours represent 80% and 20% level contributions, respectively.

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