Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA with q(2), 0.671; r(2), 0.969; CoMSIA with q(2), 0.608; r(2), 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein-ligand interaction fingerprint (PLIF) and ADMET analysis. 44 N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors.

Mesenchymal epithelial transition factor (c-Met) is an attractive target for cancer therapy. Three-dimensional pharmacophore hypotheses were built based on a set of known structurally diverse c-Met inhibitors. The best pharmacophore model, which identified inhibitors with an associated correlation coefficient of 0.983 between their experimental and estimated IC(50) values, consisted of two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic feature. The highly predictive power of the model was rigorously validated by test set prediction and Fischer's randomization method. The high values of enrichment factor and receiver operating characteristic (ROC) score indicated the model performed fairly well at distinguishing active from inactive compounds. The model was then applied to screen compound database for potential c-Met inhibitors. A filtering protocol, including druggability and molecular docking, were also applied in hits selection. The final 38 molecules, which exhibited good estimated activities, desired binding mode and favorable drug likeness were identified as potential c-Met inhibitors. Their novel backbone structures could be served as scaffolds for further study, which may facilitate the discovery and rational design of potent c-Met kinase inhibitors.

Articles you may be interested inLuminescence thermometry below room temperature via up-conversion emission of Y2O3:Yb3+,Er3+ nanophosphors J.Intense green and red upconversion emission of Er3+,Yb3+ co-doped CaZrO3 obtained by a solution combustion reactionThe Er 3þ /Yb 3þ co-doped Y 2 Ti 2 O 7 nanocrystals were synthesized by the sol-gel method. X-ray diffraction, transmission electronic microscopy, and photoluminescence spectra were measured to verify the Y 2 Ti 2 O 7 nanocrystalline produced in the sample annealed at 800 C. The anomalous slopes of the fitted line in the log-log plots for upconversion emissions and the pump-saturation effect of near-infrared emission were observed in the nanocrystalline samples. A theoretical model of practical Er 3þ /Yb 3þ co-doped system based on the rate equations were put forward and explained the experimental phenomena well. V C 2014 AIP Publishing LLC.

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The luminescence properties of osthole in the presence of spherical silver nanoparticles (AgNPs) with sizes ranging from 5 to 25 nm were investigated by means of fluorescence and absorption spectroscopic experiments, as well as time-resolved fluorescence experiments. Quenching of the fluorescence of osthole has been found to increase with a reduction in the sizes of the silver nanoparticles. Using the Gersten-Nitzan model, the theoretical and experimental results were compared, and the results are in good unity. Stern-Volmer quenching constants have also been calculated. Both dynamic quenching and static quenching mechanisms exist between osthole molecules and silver nanoparticles.

Er(3)/Yb(3)-codoped phosphate glass with compositions of (78.2-x)P(2)O(5)-14Al(2)O(3)-5Li(2)O-1K(2)O-1.8Yb(2)O(3)-xEr(2)O(3)(x=0.2,0.4,0.6) in mol. % were investigated. Judd-Ofelt (JO) intensity parameters have been calculated to predict radiative properties based on absorption spectra. The stimulated emission cross section (σ(e)) calculated according to McCumber theory was 1.50×10(-20)  cm(2), almost twice larger than values reported before. The effective line width (Δ(eff)), full width at half-maximum (FWHM) and the quality parameters for designing optical amplifier devices were listed in the table compared with other types of phosphate glass matrices. A theoretical model of a Er(3)/Yb(3)-codoped system based on rate and power propagation equations was put forward to investigate the potential advantages of the materials applied for short-length, high-gain fiber amplifiers. A simulated gain of 32.2 and 2.6  dB/cm per unit length was achieved in 12.5-cm-long fiber.

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