3D-QSAR, Docking And Molecular Dynamics Simulations Studies On Multi-targeted Src Kinase Inhibitors

The non-receptor protein c-Src tyrosine kinases play a vital role in regulating signal transduction, and the overexpression or hyperactivation of Src is correlated with malignant progression of tumors. Therefore, the development and progression of tumor could be inhibited through specifically blocking Src-mediated signal transduction. Multi-targeted kinase inhibitors with Src-inhibitory activitycan simultaneously suppress tumor cell lines of Src and related molecular targets of pathogens, which could make a more extensive biological activities and selectivity and overcome the resistance of drugs, demonstrating the great potential of the development in clinicalapplication. In recent years, the studies of the multi-targeted Src kinase inhibitorshave become a hotspot in the current international anticancer agents research. Although some progress has been made in experimental researches, the theoretical studies on the action mechanisms between these compounds and their receptors and the correlations between the structural properties of these compounds and their activities are still unclear. Hence, on the basis of the experimental results, the theoretical studies on the quantitative structure-activity relationship(QSAR), molecular docking and molecular dynamics simulations of multi-targeted Src kinase inhibitors are very significant for analyzing the action mechanism and designing novel structural and high potential anticancer multi-targeted Src kinase inhibitors.In this dissertation, theoretical studies on three dimensional quantitative structure-activity relationship(3D-QSAR) and action mechanism of three recently reported series of multi-targeted Src kinase inhibitors with anticancer activity, have been carried out using comparative molecular field analysis(Co MFA), comparative molecular similarity analysis(Co MSIA), molecular docking and moleculardynamics simulations. 3D-QSAR models with significant statistical quality and robust predictive power were established. Moreover, probable action models between these compounds and their receptors as well as the key residues in the binding pockets were also obtained. These results could offer some useful theoretical reference for designing high potential anticancer multi-targeted Src kinase inhibitors and experimental researchers.Four chapters are included in this dissertation.The first chapter is introduction. The structure characteristics and functions of Src kinaseare briefly reviewed. The possible action mechanismsof several typical kinds of anticancer multi-targeted Src kinase inhibitors,as well as their currentstatus and development on theoretical studies are systematically summarized. Meanwhile, the developmental history, the basic principles and commonly computational methods of computer-aided drug design(CADD)as well as the significant of this titleare briefly introduced and clearly elucidated.In the second chapter,molecular docking, molecular dynamics(MD) simulation and binding free energy calculation were performed to the study of a series of indole derivatives as dual c-Src/IGF-1R inhibitor. The appropriate binding modes and conformations of these compounds interacting with both Src and IGF-1R kinases were revealed by docking studies, and the binding details of the compounds with different activities were determined by MD simulations.Meanwhile, the reasons for the inhibitors with dual Src/ IGF-1R inhibitory activities were explored by comparing the differences and similarities of Src and IGF-1R kinases. The major driving force for the binding to Src and IGF-1R and the key amino acid residues at the binding pockets were also revealed by binding free energy calculation and the energy decomposition. Finally, the action mechniams between these inhibitors and their receptoes were discussed in detail. These results can provide a helpful theoretical reference for further synthesizing novel dual Src/ IGF-1R inhibitory activities.In the third chapter, a series of N9-arenethenyl purines with potent inhibitory activities on DFG-in and DFG-out conformations of c-Srcand Abl enzymes were selected to carried out a theorectical study by using 3D-QSAR, moleculardocking and molecular dynamics(MD) simulations.The obtained Co MFA models with satisfactory internal and external predictability were established and the structural features affecting the activities were discussed in detail. The appropriate binding modes and conformations of these compounds interacting with both DFG-in and DFG-out Src and Abl kinases were revealed by docking studies,the comparisions of the differences and similarities of Src and Abl kinases as well as the structural differences between DFG-in and DFG-outconformations were also analyzed. Thekey amino acid residues were identified by docking studies, and the detailed binding modes of thecompounds with different activities were determined by MD simulations. The MM-PBSAenergy decomposition revealed the major driving force for the binding of the DFG-in and DFG-out compoundsto Src and Abl and the key amino acid residues at the binding pockets. These results can offer useful references for designing novel potential DFG-in and DFG-out dual Src/Abl inhibitors.In the fourth chapter, a series of pyrimidine/quinazoline furnished molecules as dual NF-κB and AP-1 inhibitors were selected to carried out a theorectical study by 3D-QSAR, molecular docking and MD simulations. The present Co MFA model showing significant statistical quality and satisfying predictive ability was established. Meanwhile, the most probable binding sites of two receptors had been identified by docking and MD simulations,the key residues for achieving strong binding were also revealed by MD studies. Above results can provide significant insight into the development of novel potential dual NF-κB /AP-1 inhibitors.In the fifth chapter, the summary and prospect were briefly presented for this work.