A theoretical study on the two-dimensional, threedimensional 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 cSrc 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 threedimensional-quantitative structure-activity relationship models. The leave-one-out cross-validation q 2 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 IC 50 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-dimensionaland three-dimensional-quantitative structureactivity 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 R 2 , increasing the negative charge of the first atom of substituent R 1 and the net charge of the C 15 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.Key words: comparative molecular field analysis, c-Src, docking study, ethynyl-3-quinolinecarbonitriles, quantitative structure-activity relationship Received 6 March 2011, revised 11 February 2012 and accepted for publication 25 February 2012 c-Src, the oldest and most studied class of non-receptor protein tyrosine kinase, is the prototypic member of a family of kinases (Src Family Kinases, SFKS), which plays a pivotal role in signaling transduction pathways controlling cell growth, proliferation, invasion, and apoptosis. In most normal cells, c-Src is highly regulated at low levels and maintained in an inactive conformation. However, in many human tumor types, c-Src kinase is unregulated (1,2). Recently, many reports have shown that the over-expression or over-activation of c-Src is associated with a variety of human solid tumors, including breast (3), colo...

The development of selective lymphocyte‐specific kinase (Lck) inhibitors has attracted much attention for the research of the treatment of T‐cell mediated autoimmune and inflammatory diseases. In the present work, three‐dimensional quantitative structure–activity relationship (3D‐QSAR) analyses are performed on a novel series of 4‐amino‐6‐benzimidazole‐pyrimidines acting as Lck inhibitors. The established 3D‐QSAR models show significant statistical quality and satisfactory predictive ability, with high q2 and R2 values: the comparative molecular field analysis (CoMFA) model (q2 = 0.802, R2 = 0.991), and the comparative molecular similarity indexes analysis (CoMSIA) model (q2 = 0.731, R2 = 0.982). The systemic external validation indicates that both CoMFA and CoMSIA models are quite robust and possess high predictive abilities with Rpred2 values of 0.881 and 0.877, rm2 values of 0.897 and 0.847, rm(LOO)2 values of 0.897 and 0.850, and rm(overall)2 values of 0.897 and 0.854, respectively. Several key structural features accounting for the inhibitory activities of these compounds are discussed. Based on established models and design considerations, six new compounds with significantly improved activities are theoretically designed, which still await experimental confirmation and evaluation. These theoretical results may provide a useful reference for understanding the action mechanism and designing novel potential Lck inhibitors. © 2014 Wiley Periodicals, Inc.

A theoretical study on binding orientations and quantitative structure–activity relationship (QSAR) of a novel series of alkene‐3‐quinolinecarbonitriles acting as Src inhibitors has been carried out by using the docking study and three‐dimensional QSAR (3D‐QSAR) analyses. The appropriate binding orientations and conformations of these compounds interacting with Src kinase were revealed by the docking studies, and the established 3D‐QSAR models show significant statistical quality and satisfactory predictive ability, with high R2 values and q2 values: comparative molecular field analysis (CoMFA) model (q2 = 0.748, R2 = 0.972), comparative molecular similarity indices analysis (CoMSIA) model (q2 = 0.731, R2 = 0.987). The systemic external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with $ R{^2}_{\!\!\!\rm pred} $ values of 0.818 and 0.892, $ {r^2}_{\!\!\!\rm m} $ values of 0.879 and 0.886, $ {r^2}_{\!\!\!\rm m(LOO)} $ values of 0.874 and 0.874, $ r^2_{\rm m(overall)} $ values of 0.879 and 0.885, respectively. Several key structural features of the compounds responsible for inhibitory activity were discussed in detail. Based on these structural factors, eight new compounds with quite higher predicted Src‐inhibitory activities have been designed and presented. We hope these theoretical results can offer some valuable references for the pharmaceutical molecular design as well as the action mechanism analysis. © 2012 Wiley Periodicals, Inc.

In recent years, the development of dual or multi-targeted inhibitors has captured extensive attention of research for treating of malignancies. In this paper, three-dimensional quantitative structure-activity relationship and docking studies were performed on 87 pyrazolo[3,4-d]pyrimidines as dual Src/Abl inhibitors. The appropriate binding orientations and conformations of these compounds interacting with both Src and Abl kinases were revealed by docking studies, and the established optimum CoMFA models yielded q(2) =0.856, R(2) =0.966 for Src and q(2) =0.869, R(2) =0.974 for Abl, and the best CoMSIA models gave q(2) =0.877, R(2) =0.979 for Src and q(2) =0.885, R(2) =0.982 for Abl. Systemic external validations further confirm the satisfactory predictive power of these models, producing R(2) pred values of 0.872 and 0.865 for Src, 0.876 and 0.867 for Abl, r(2) m values of 0.832 and 0.928 for Src, 0.838 and 0.904 for Abl, respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that the hydrophobic and electrostatic interactions of compounds play significant roles for the inhibitory activity against both Src and Abl kinases. Some structural factors influencing the activities of these compounds were discussed in detail. The key amino acids impacting the receptor-ligand interactions have been identified. These theoretical results can offer useful references for designing novel potential dual Src/Abl inhibitors.