Theoretical Studies on Pyrazolo[3,4-d]pyrimidine Derivatives as Potent Dual c-Src/Abl Inhibitors Using 3D-QSAR and Docking Approaches.

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.

Theoretical studies of QSAR and molecular design on a novel series of ethynyl-3-quinolinecarbonitriles as SRC inhibitors.

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.

[Effect of nuclear factor-kappa B decoy oligodeoxynucleotides on IL-10, IL-13 and nuclear factor-kappa B protein expressions in rabbits with severe lung contusion].

OBJECTIVE: To explore the effect of nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides (ODN) on serum NF-κB, IL-10, IL-13 and pulmonary NF-κB protein expression in rabbits with severe lung contusion. METHODS: Forty New Zealand rabbits were randomly divided into severe lung contusion group (group A, n=12), lung contusion with NF-κB scrambled decoy ODN group (group B, n=12), lung contusion with sense NF-κB decoy ODN group (group C, n=12), and normal control group (n=4). After establishment of the contusion injury model, the sense and scrambled NF-κB decoy ODN were infused into the rabbits via the jugular vein accordingly. Serum NF-κB, IL-10, and IL-13 and NF-κB protein expressions in the lung tissue were detected before and at 1, 2, 3, and 4 h after the contusion. RESULTS: Two hours after sense NF-κB decoy ODN intervention, the expression of NF-κB began to decrease and reached the lowest level at 3 h; pulmonary IL-10 and IL-13 expressions decreased at 1 h after contusion, to the lowest level at 2 and 4 h, respectively. After sense NF-κB decoy ODN intervention, the expression of IL-10 and IL-13 increased and NF-κB protein expression decreased significantly in comparison with those in groups A and B (P<0.01). CONCLUSION: Sense NF-κB decoy ODN can significantly reduce the serum NF-κB expression, increase serum IL-10 and IL-13 levels and decrease pulmonary NF-κB protein expression in the early stages after severe lung contusion in rabbits.

[A clinical study of lobectomy with minimally invasive incision].

OBJECTIVE: To study the application of small thoracic incision for lobectomy with effects comparable to that of conventional incision. METHODS: A total of 386 patients with lung tumors were prospectively randomized into thoracic small incision group (n=184; average length of incision, 12.7 cm) and standard thoracic incision group (control group, n=152). The incision length, operation time, intra-operative bleeding volume, postoperative drainage volume, transfusion, hemostatic dosage, ambulation time, hospital stay and major complications were compared between the two groups. RESULTS: All of the indices in small incision group were significantly better than those of the control group (P<0.01) except the operation time (P>0.05). No severe complications occurred in small incision group, and in 4 cases conventional thoracotomy was performed instead due to adhesion or giant tumors. CONCLUSIONS: Muscle-sparing thoracic small incision can achieve excellent clinical result and has such advantages as less invasiveness, reduced bleeding volume, pain and hospital stay, less complications, and better postoperative appearance. This procedure meets the requirements of lobectomy and provides an alternative for routine lobectomy for pulmonary tumors.