Design And Mechanisms Of CDKs-targeted And Mitochondria-targeted Anticancer Drugs

The treatment of cancer is one of the greatest challenges of the 21 st century.Anti-cancer therapy targeted to the hallmarks of cancer cells can efficiently kill cancer cells and reduce the damage to normal cells.Uncontrolled cell proliferation is one of the basic characteristics of cancer,and cyclin-dependent kinases(CDKs)appear to be attractive anti-cancer targets due to their vital regulatory role in cell cycle progression.Mitochondria are the main organelle for ATP,as well as the cell death regulatory center.Cancer cells can be selectively killed by targeting to cancer mitochondria,which differ from normal ones.In this work,a series of anti-cancer compounds targeted to CDKs and mitochondria were designed,their physiological activities were evaluated and their mechanism of action was investigated.In the process of drug design and mechanism interpretation,we study the structure of the targets and drug-biomacromolecular interaction modes by molecular simulation methods,and combine simulation results with experimental methods to expand the application of molecular simulation methods in drug design.The main research content of this paper is divided into the following five chapters:Chapter 1: The basic hallmarks of cancer cells were introduced in detail,the theoretical basis of two anti-cancer strategies targeted to CDKs and mitochondria was reviewed,and the research progress of anti-cancer drugs targeted to CDKs and mitochondria was systematically introduced.On this basis,this paper expounds the background and innovation of the topic.Chapter 2: Molecular dynamics simulations were used to study the dynamic structural characteristics and free energy landscape of CDK6-Vcyclin complex.It was found that there were open and closed states for CDK6-Vcyclin complex,and Thr177 phosphorylation on A-loop can significantly reduce the energy barrier of the conformational change of CDK6-Vcyclin,which might be the mechanism of its phosphorylation activation.On this basis,the binding modes of ten inhibitors with CDK6 were discussed,and it was found that specific CDK6 inhibitors tended to bind with the closed state,while non-specific inhibitors tended to bind with the open state.Chapter 3: Potential CDK1 inhibitors were screened from the Maybridge compound library containing 97400 molecules by molecular docking method.In the screening process,the structures of CDK1 binding pocket in multiple states were fully considered,and the binding modes were verified by MD simulations.Finally,18 candidate inhibitors were selected for biological tests.The biological activity of the candidate inhibitors was evaluated by CDK1 enzyme activity inhibition test,cell cycle test and cell proliferation test.Chapter 4: We systematically investigated the biological activities of the identified CDK1 inhibitor CS1-2,including the selectivity to CDK1,cell cycle arrest activity,anti-tumor activity and mechanisms.It was found that CS1-2 induced mitotic arrest,leading to the occurrence of endo-replication and polyploid cells,and eventually apoptosis.The synergistic effects of CS1-2 and DNA damage agents were good.Chapter 5: Two F16 isomers(o-F16 and m-F16)were obtained by changing the connection orientation of the pyridine and indole rings of F16 molecules,and it was found that o-F16 and F16 showed strong uncoupling activities,while m-F16 showed poor activity.The results of molecular dynamics simulations and quantum calculation show that the difference of uncoupling activity arose from the difference in proton dissociation energies rather than the difference in transmembrane energy barrier.F16 molecule can bring the fluorescent molecule BODIPY into mitochondria and realize the dual functions of anti-tumor and imaging.