Molecular Docking Studies On The Anti-tumor Effects Of JAK Kinase Inhibitors

In recent years, the incidence of malignant tumor continues to rise, mortality remains high, which constitutes a serious threat to human health, conquer cancer has become one of the key research topics in the field of medicine. The present research idea is first to determine appropriate anti-tumor targets, then aimed at the target for high-efficiency and harmfulless antitumor active ingredient. In numerous anti-tumor targets, cell signal transduction of JAK kinase is one of the study of the popular targets. JAK kinase includes members of the family of four: JAK1 protein, JAK2 protein, JAK3 protein and TYK2 protein. Listed anti-tumor drugs based on the targets are also many, but the selective of most of the research JAK kinase inhibitors is not high, inhibition of protein is not strong, also may produce a lot of toxic effects.Reason may be that the research on the mechanism of action of these specific inhibitor molecules is not deep enough. Many JAK kinase inhibitors are often unable to match the active site of the target protein in space, thus cannot play a strong biological effects, and even produce some toxicity.Based on this, this paper on the basis of reference, using molecular docking method to simulate the have been listed or in clinical studies of 11 JAK kinase inhibitor molecules and four JAK kinase family member protein binding mode and interaction. The main mechanism of inhibitory effect on target protein for JAK kinase inhibitor molecules is discussed from the molecular level, the reasons for the low selectivity and low activity of the various inhibitors were also analyzed, and put forward the idea of the possible structure modification of the inhibitors.Experimental study showed that the JAK kinase family of four members of the protein belongs to the same family, but their active sites exist certain differences, each of which plays the corresponding biological effects, the inhibitors only occupy all the binding sites in the active cavity, which can show the strong binding capacity and strong inhibitory activity of the target protein.The crystal structure of JAK1 protein and JAK2 protein were similar, and the active sites were composed of P-loop region, Hinge region and A-loop region. The selectivity of inhibitors to these two proteins is poor, and the binding capacity is similar. The active region of JAK3 protein is composed of glycine rich region(Gly-loop) and “hinge region”. Inhibitor molecules only occupy the two loci simultaneously to maximum effect. The active site of TYK2 protein is composed of alarge pocket and an open region P-loop region, which can exert a strong inhibitory activity of TYK2 protein as long as these two sites are firmly occupied.Based on the docking conformation analysis, we found that the polycyclic molecules with similar planar structure are highly selective for the JAK1 protein,JAK2 protein and JAK3 protein, but poorly for the TYK2 protein.