3D-QSAR,Molecular Docking And Molecular Dynamics Simulation Study Of Novel Kinase Inhibitors

Tyrosine kinase JAK3 is an intracytoplasmic non-receptor protein kinase that only exists in bone marrow and lymph system.It plays a very important role in the immune regulation factor receptor JAK-STAT signal pathway containing ? chain,which is a new target for the discovery of small molecule immune inhibitors.In this paper,60 JAK3 kinase inhibitors collected with activity data were studied using various computer simulation methods such as three dimensional quantitative structure-activity relationship(3D-QSAR),molecular docking,molecular dynamics simulation and so on.We established the reliable 3D-QSAR model,the optimal correlation between the results of comparative molecular field analysis(CoMFA)and comparative molecular similarity analysis(CoMSIA)models are:q2 = 0.715;r2 = 0.992 and q2 = 0.739;r2 = 0.995.According to the contour map analyses of fIve force fIelds,we obtained the structure information of the compounds and designed new compounds with potential high activity.The results of molecular docking show that crucial electrostatic interactions are formed between ligand and residues Gly829,Va1836,Ser835,Asp967 and Lys830;hydrophobic amino acids Leu828,Cys909,Arg953,Ile955,Leu956,A1a966 and Asn954 in the binding cavity also play important roles in inhibitor potency.Besides,the MD simulation study further validates the results of molecular docking;on the basis of MD simulation stable conformation,the binding free energy was calculated indicating that the most important contribution is the ?Evdw to the overall binding free energy.Therefore,the results of this study provide a very important theoretical guidance to guide the design of new molecules.Src homology(SH2)domain is an important part of tyrosine protein kinase signal transduction pathway.SH2 domain participating in abnormal signal pathway can cause many human cancers and genetic diseases.So,the SH2 domain can be used as a potential drug target,and its inhibitors can be a new anti-cancer drug with molecular targeting.With the aid of computer aided simulation design software,we carried out the theretical research study to SH2 domain knase inhibitors.A reliable 3D-QSAR model was builted(CoMFA:q2= 0.566,r2? 0.957;CoMSIA:q2= 0.664,r2= 0.967),and molecular docking method was used to study the possible mechanism between the ligand and the receptor protein.According to the information obtained,the new potential high inhibitor molecules were designed.