title: Theoretical studies of QSAR and molecular design on a novel series of ethynyl-3-quinolinecarbonitriles as SRC inhibitors.
abstract: A theoretical study on the two-dimensional, three-dimensional quantitative structure-activity relationships and docking analysis of a novel series of ethynyl-3-quinolinecarbonitriles acting as Src inhibitors has been carried out. To correlate the c-Src kinase-inhibition activity of these compounds with the two-dimensional and three-dimensional structural properties for 39 known compounds, some excellent quantitative structure-activity relationships models with satisfying internal and external predictive abilities were established. A combined method of the density functional theory, molecular mechanics and statistics as well as the comparative molecular field analysis was applied to develop two-dimensional- and three-dimensional-quantitative structure-activity relationship models. The leave-one-out cross-validation q² values of two-dimensional-quantitative structure-activity relationship and comparative molecular field analysis models are 0.834 and 0.812, respectively. The predictive abilities of these models were further validated by the test set including 10 compounds, and the predicted IC₅₀ values were in a good agreement with the experimental ones. The appropriate binding orientations and conformations of these compounds interacting with c-Src kinase were also revealed by the docking study. Based on two-dimensional- and three-dimensional-quantitative structure-activity relationship results along with docking analysis, some important factors responsible for inhibitory activity of this series of compounds were discussed in detail. These factors can be summarized as follows: selecting certain large-size substituent R₂, increasing the negative charge of the first atom of substituent R₁ and the net charge of the C₁₅ atom on ring-C will enhance the activity. Meanwhile, the interaction information between protein and ligand was also revealed in detail. These results help to understand the action mechanism and designing novel potential Src inhibitors. Based on the established models and some designing considerations, three new compounds with rather high predicted Src-inhibitory activity have been theoretically designed and presented to experimenters for reference.
authors.affiliation: Department of Cardiothoracic Surgery, Second Affiliated Hospital of Guangzhou Medical College, Guangzhou 510260, China.
authors.forename: Dan Qing
authors.initials: DQ
authors.lastname: Fang
authors.forename: Wen Juan
authors.initials: WJ
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Guo Hua
authors.initials: GH
authors.lastname: Zeng
authors.forename: Kang Cheng
authors.initials: KC
authors.lastname: Zheng
mesh_terms: D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D056004:Molecular Dynamics Simulation; D009570:Nitriles / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry*; D019061:src-Family Kinases
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases