Studies On The Interactions Between Some Natural Products And Pyrimidines And Lck Kinase

Lymphocyte-specific kinase (Lck) is a non-receptor protein tyrosine kinase in theSrc-family with restricted expression in T-cells and natural killer (NK) cells. Many reportshave shown that the activation of TCR signaling by Lck may arouse a cascade ofdownstream signaling pathways and lead to the production and release of cytokinesincluding interleukin-2(IL-2) and interferon-γ, which causing the corresponding immuneresponses. Normally, the expression and activity of Lck is limited. However, whenstimulated by some outside factors, its abnormal expression and activity would cause someT-cell mediated autoimmune diseases, inflammation and allergic diseases. In addition, theectopic expression of Lck kinase in other cells can induce cell pathological changes, such ascolon cancer and small cell lung cancer. Therefore, the Lck selective inhibitors would beexpected to provide a promising approach for treating T-cell mediated autoimmune andinflammatory diseases and chronic organ transplantation rejection. Many natural productsand compounds possess good inhibition to Lck kinase, such as Emodin, Lavendustin A,Damnacanthal, Piceatannol, flavoid, benzimidazole-pyrimidines, benzothiazoles andaminopyrimidine derivatives. Hence, the research and development of these naturalproducts and compounds could be used to find the new Lck inhibitors. Although someprogress has been made in experimental researches, so far the theoretical studies on actionmechanisms between these compounds and their receptors and the correlations betweenstructures of these compounds and their inhibitory activities are still unfrequent. So it is a very interesting and significant work to carry out the studies on quantitativestructure-activity relationship (QSAR), docking, action mechanism and molecular designfor these compounds.In this dissertation, theoretical studies on three dimensional quantitative structureactivity relationship (3D-QSAR) and action mechanism of some natural products and seriesof compounds with anti-inflammatory activity, have been carried out using comparativemolecular field analysis (CoMFA), comparative molecular similarity analysis (CoMSIA)docking analysis and molecular simulation. The interaction mechanism between theseseries of natural products and Lck kinase were studied, to analyze the differences of theirLck inhibitory activities. Meanwhile, QSAR models showing a significant statistical qualityand satisfying predictive ability were established, and appropriate binding sites and modelsof these compounds interacting with their receptors were also revealed. Based on theseresults, some new compounds with higher activity have been designed. We hope thesetheoretical results can be confirmed by experimental work.Four chapters are included in this dissertation.The first chapter is introduction. The progress in the study of Lck kinase inhibitors, isbriefly reviewed. The research status on some reported Lck kinase inhibitors and the actionmechanism are also systematically summarized. The general research situations of Chinesemedicine and natural products at home and abroad are briefly introduced. And theprogression, basic principles and methods of computer-aided drug design are brieflyintroduced. Thus the significance of the theoretical studies on the quantitativestructure-activity relationship (QSAR) and action mechanism of novel Lck inhibitors iselucidated.In the second chapter, some series of extracts of traditional medicines were selected tostudy their interaction with Lck kinase using molecular dynamics and docking studiesmethods. The possible binding mode and action mechanism between these natural productsand Lck kinase were analyzed. The differences of their Lck inhibitory activities wereillustrated. These researches could provide some theoretical guidances for the optimizationand structure modification of these natural products. In the third chapter, a series of benzimidazole-pyrimidines analogues as Lck inhibitorswere selected to perform3D-QSAR and molecular docking studies. The3D-QSAR modelswith significant statistical quality and good predictive ability were established and the bestdocking conformations of these compounds were obtained. The contour maps of3D-QSARwere in good accordance with the receptor environment in the binding site. Based on theresults of3D-QSAR and docking studies, some new compounds with more potentinhibitory activity were theoretically designed.In the fourth chapter, a series of aminopyrimidine derivatives with three-targetedLck/Src/KDR inhibitory activities were selected to study the possible structure-activityrelationship and interaction between inhibitors and Lck/Src/KDR proteins in terms ofstatistical and microscopic viewpoint by using a combined3D-QSAR and docking analysis.Firstly,3D-QSAR models showing significant statistical quality and satisfying predictivepower were established and main factors influencing the anti-inflammatory activities ofinhibitors were discussed in detailed. Meanwhile, the relationships betweenaminopyrimidine derivatives and Lck/Src/KDR kinases were obtained through moleculardocking. In addition, the internal reasons for the inhibitors with three-targetedLck/Src/KDR inhibitory activities were explored by comparing the differences andsimilarities of Lck/Src/KDR kinases. These results can provide a helpful theoreticalreference for further synthesizing novel compounds with three-targeted Lck/Src/KDRinhibitory activities.Finally, the conclusions, deficiencies and prospect were briefly summarized for thiswork.