title: QSAR studies on 4-anilino-3-quinolinecarbonitriles as Src kinase inhibitors using robust PCA and both linear and nonlinear models.
abstract: Quantitative structure-activity relationship (QSAR) studies have been carried out on 4-anilino-3-quinolinecarbonitriles, a set of novel Src kinase inhibitors, with the aim of dissecting the structural requirements for Src inhibitory activities. After outlier identification using robust principal component analysis (robust PCA), linear models based on forward selection combined with multiple linear regression, (FS-MLR), enhanced replacement method followed by multiple linear regression (ERM) and a nonlinear model using support vector regression (SVR) were constructed and compared. All models were rigorously validated using leave-one-out cross-validation (LOOCV), 5-fold cross-validations (5-CV) and shuffling external validation (SEVs). ERM seems to outperform both FS-MLR and SVR evidenced by better prediction performance (n = 35, R(2)(training) = 0.918, R(2)(pred) = 0.928). Robustness and predictive ability of ERM model were also evaluated. The generated QASR model revealed that the Src inhibitory activity of 4-anilino-3-quinolinecarbonitriles could be associated with the size of substituents in the C7 position and the steric hindrance effect. The results of the present study may be of great help in designing novel 4-anilino-3-quinolinecarbonitriles with more potent Src kinase inhibitory activity.
authors: Pharmaceutical Engineering Institute, School of Chemistry and Chemical Engineering, Southeast University, 2 Sipailou, Nanjing 210096, China.
authors: Min
authors: M
authors: Sun
authors: Youguang
authors: Y
authors: Zheng
authors: Hongtao
authors: H
authors: Wei
authors: Junqing
authors: J
authors: Chen
authors: Min
authors: M
authors: Ji
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D016014:Linear Models; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology; D017711:Nonlinear Dynamics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019061:src-Family Kinases