3D-QSAR,Molecular Docking And Molecular Dynamics Simulation Studies Of Selective Janus Kinase 3 Inhibitors

The non-receptor tyrosine protein kinase JAK3 is mainly expressed in hematopoietic cells in the human body and it played an important role in the intracellular processes of hematopoiesis and immune regulation in the human body.In recent years,it represents a promising target for the treatment of immune diseases and cancers.However,there is no highly selective inhibitors of JAK3 has been developed.Inadequate selectivity of JAK3 inhibitors may lead to serious adverse reactions.Therefore,designing and developing highly selective JAK3 inhibitors have become a key issue in this field.At present,a series of substituted pyrimidine JAK3 selective covalent inhibitors have been reported in the literature,they possess high selectivity for JAK3,but the theoretical studies on the mechanisms between these compounds with the structure,the interaction between the compounds and the receptor still not very clear.Use computer-aided drug design methods to perform molecular modeling studies on these compounds will help to improve the mode of combine of JAK3 inhibitors and receptor proteins and provide information on the design and optimization of novel JAK3 selective inhibitors.In this paper,52 pyrimidine compounds reported to be highly selective and active for JAK3 were selected from the literature.They were theoretically studied by molecular docking,molecular dynamics and three-dimensional quantitative structure-activity relationships.Molecular docking and molecular dynamics were used to explore the binding relationship of these compounds and receptor proteins and the structural features that play a key role in the stability of the binding;two high-reliability and predictive capabilities models were obtained using three-dimensional quantitative structure-activity relationships.The 3D-QSAR models obtained the relationship between the structure and activity of the compounds,and used this as a clue to optimize the structure of the compound and designed 16 new compounds.We hope that this study will provide effective information for the design of novel inhibitors of JAK3.In the chapter 1,it mainly summarized the etiology and pathogenesis of rheumatoid arthritis and introduced the JAK-STAT signaling pathway plays a key role in the pathogenesis of rheumatoid arthritis,especially the unique position and role of JAK3 kinase in the signaling pathway,and the research progress on JAK3 kinase inhibitors.Besides,it briefly introduces the commonly used methods and principles of computer-aided drug design and proposes of this topic.In the chapter 2,fifty-two pyrimidine compounds were selected from the literature,and they were subjected to molecular docking and molecular dynamics simulations.The mode of binding between the compound and the receptor was explored,and the key residues affecting the stability of them were found.In the chapter3,a three-dimensional quantitative structure-activity relationship study was performed on the above 52 pyrimidine compounds,and two models with high reliability and predictability were constructed.The models were analyzed to obtain the relationship between the structure and activity of the compound.Based on these information,the structure of the compound was optimized.Sixteen new compounds were designed and their activities and ADMET predictions were performed.In the chapter 4,the summary and prospects were concluded in brief for this work.