3D QSAR studies on a series of potent and high selective inhibitors for three kinases of RTK family.
For targets belonging to the same family of receptors, inhibitors often act at more than one biological target and produce a synergistic effect. Separate CoMFA and CoMSIA models were developed from our data set for the KDR, cKit and Tie-2 inhibitors. These models showed excellent internal predictability and consistency, and validation using test-set compounds yielded a good predictive power for the pIC(50) value. The field contour maps (CoMFA and CoMSIA) corresponding to the KDR, cKit and Tie-2 kinase subtypes reflected the characteristic similarities and differences between these types. These maps provided valuable information to facilitate structural modifications of the inhibitor to increase selectivity for the KDR over cKit and Tie-2.
Cao
Hongyu
H
Liaoning Key Laboratory of Bio-organic Chemistry, Dalian University, Dalian 116622, China.
Zhang
Huabei
H
Zheng
Xuefang
X
Gao
Dabin
D
D001665:Binding Sites; D003196:Computer Graphics; D003198:Computer Simulation; D015195:Drug Design; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000145:classification; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry
D008024:Ligands; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2