Theoretical Studies Of 3D-QSAR, Docking And Molecular Dynamics Simulations Studies On Abl Kinase Inhibitors

Abelson(Abl) regards as a non-receptor protein tyrosine kinase, playing a critical role in regulating human cellular activity, such as cell differentiation, division, adhesion and stress response, etc. For hematopoietic stem cell, the abnormal breakpoint cluster region(Bcr) protein located at the N terminal of Abl kinase leads to the overexpression or hyperactivation of Abl kinase, which is mainly related with the progression of Chronic myelocytic leukemia(CML). Therefore, specifically blocking Bcr-Abl-mediated signal transdection is an effective way to treat the CML. As a first-generation Bcr-Abl kinase inhibitor, Imatinib is approved to successfully use in clinical treatment and effective for most patients with CML. Although clinical remission has been achieved with imatinib, many patients relapse because of the point mutations in the Bcr-Abl kinase domain. T315 I mutation is the most difficult to be overcome and to date less compounds can inhibit cases with T3151 mutation. In recent years, the discovery of potent Bcr-Abl inhibitors targeting T315 I mutation become a key development field to treat the most clinically promising anti-T315 I therapies. So far, benzothiazole/benzimidazole-based derivatives, benzamide-based derivatives and pyrazolo[3,4-d] pyrimidines derivatives shows excellent inhibitions toward Bcr-Abl kinase T315 I mutation and the native kinase., indicating that the great potential to develop these compounds as novel anti-T315 I Bcr-Abl inhibitors. Though several progresses have been achieved in experimental researches now, the theoretical studies on the mechanisms of these compounds toward Bcr-Abl kinase and the structural characteristics affecting their antileukemia bioactivities still keep largely unknown. Thus, it is a momentous work to analyze the action mechanism and design novel anti-T315 I Bcr-Abl kinase inhibitors by performing the theoretical studies of QSAR, molecular docking and molecular dynamics simulations.In this paper, three series of compounds with high inhibitory bioactivies, including some three Abl_wt/T315 I and c-Src inhibitors, have been chosen to perform 3D-QSAR and action mechanism by using comparative molecular field analysis(Co MFA), comparative molecular similarity analysis(Co MSIA), molecular docking and MD simulation. 3D-QSAR models with the excellent qualit y and robust predictive ability were constructed, the structural features impacting the activities and the probable binding models connecting these compounds with the receptors were observed. These results could provide helpful reference for designing novel Abl_T315I kinase inhibitors with stronger bioactivity.For chapters are included in this dissertation.The first chapter is introduction. The structural features and biological action of Bcr-Abl kinase are briefly described. The research status and action mechanism of several kinds of Bcr-Abl kinase inhibitors have summarized. Besides, the development, the basic principles and commonly calculated approaches of CADD were introduced in brief, and the significance to carry out this work was also clearly elucidated.In the second chapter, 3D-QSAR, molecular docking and molecular simulation were carried out to the study of a series of benzothiazole/benzimidazole derivatives as Bcr-Abl kinase inhibitors with T315 I mutant. The probable binding modes of the selected compounds interacting with receptor protein were observed by docking studies. The 3D-QSAR model was built with reliable statistical quality, and the key structural features were also discussed. With the method of MD simulation, we further verified the binding models of complexes, and discovered the key amino acids located around the binding pocket. Based on the aboved results, four new compounds with more potent inhibitory activities were designed and their biological activities were predicted.In the third chapter, a series of benzamide analogues as dual Abl_wt and Abl_T315I kinase inhibitors were chosen to carry out CoMSIA, molecular docking and MD simulation studies. The suitable binding models the studied compounds with both Abl_wt and Abl_T315I kinases were obtained by the docking studies. The different bioactivities of the compounds with dual kinase were carefully analyzed by comparing the differences of structures of Abl_wt and Abl_T315I kinases. The Co MSIA models were constructed with the reliable statistical quality, and the key structural features influencing the bioactivity were also discussed. Comparing the MD simulation of six representative compounds with Abl-wt and Abl-T315 I complexes, we expounded the effects of each substituent on inhibitory activity,and analyzed the reason of the binding conformations and different energy of these compounds with both Abl_wt and Abl_T315I kinases.In the fourth chapter, a series of pyrazolo[3,4-d] pyrimidines derivatives with three-targeted Abl_wt/ Abl_T315I/c-Src inhibitory bioactivity were selected to perform the theorectical study of Co MFA, molecular docking and MD simulation. The Co MFA models were established with the reliable statistical quality, and analyzed the important structural factors to affecting bioactivity were also analyzed in detailed. The optimized binding sites with Abl_wt, Abl_T315I and c-Src kinases were obtained by molecular docking. Moreover, the internal relationships of these conpounds with Abl_wt/T315I/c-Src were observed by comparing the differences and similarities of the active sites of Abl_wt/T315I/c-Src kinases. In addition, the binding poses of three receptors were further confirmed by MD simulations. With decomposing of the binding energies, the key residues of three receptors impacting inhibitory bioactivity had found.In the fifth chapter, the summary and prospects were concluded in brief for this work.