Abstract:The c-Jun N-terminal kinase 3 (JNK3) has been shown to mediate neuronal apoptosis, which makes inhibiting this isoform a promising therapeutic target for neurodegenerative diseases. Due to the high sequence similarity among the JNK isoforms and fellow MAP kinase family member p38, exploring the selectivity mechanism of inhibition is crucial to develop efficacious and safe compounds. In this work, molecular basis of the JNK3 inhibition and selectivity over p38 of two aminopyrazole inhibitors (SR3576 and SR3451) was investigated using combined molecular modeling methods, including molecular docking, molecular dynamics simulations and binding free energy calculation. The calculated binding free energies are well consistent with the experimental inhibition activity. It also indicated that the aminopyrazole inhibitors better occupied the smaller binding site of JNK3 compared with that of p38. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy decomposition analysis suggested that the residues Met146, Val196 and Leu206 in the binding site of JNK3 are responsible for the high selectivity of inhibitors. We expect that the obtained results here would be helpful to develop potential JNK3 inhibitors with promising selectivity.

Abstract:With 3G communication technology developing rapidly, there is an organic combination—relay station, which gets the various wireless techniques together and makes a seamless connection system to meet future market demand. For the situation of the mountain district, after the diffraction loss is analyzed, we apply computer simulation to justifying the existing and location of diffraction peak. According to the area of the region and the number of users, we can calculate the minimum amount of relay stations with the analysis above. The models can not only decrease the overlapping coverage to a great extent but also weaken the interference.