Virtual Screening Of The Novel Cdc25Inhibitors And Computational Study Of The Enzyme Inhibition Mechanism

Cdc25phosphates is an essential regulator in the cell cycle. Its over expression in various human cancer has been observed and reported, which makes Cdc25phosphates a potential target for anticancer therapy. Computer aided drug design and molecular modeling has been applied in the study of the phosphates and its inhibitors, as well as other interactions between biomacromolecule and compounds. We conducted a virtual screening of Cdc25phosphates A novel inhibitors using combination of pharmacophore modeling and molecular docking. The cytotoxicity and enzyme inhibition of all potential compounds were measured. When the study goes to the inhibition mechanism of the Cdc25phosphates, a reliable crystal structure of Cdc25phosphates B and inhibitor NSC663284were used as the model system. One stable binding site of the inhibitor was identified through systematic molecular dynamics study. The stability was studied and its mechanism was proposed through statistical analysis of relative trajectories. Moreover, three different biomacromolecular systems were studied through both experiments and molecular docking. The combination of theoretical analysis and experimental measurement, as well as the expansion of the application of molecular docking, was investigated and discussed through the sample systems. Thus, the work has been described by the following five chapters:Chapter One:This chapter gives the background of the current study of the Cdc25phosphates and its inhibitors, as well as the relative technology used in computational chemistry and molecular modeling. The intension and innovation of our work were presented based on the introduction.Chapter Two:This chapter introduced the discovery of novel Cdc25A inhibitors through virtual screening of database MaybridgeTM, including building of two pharmacophore models and molecular docking.21compounds were obtained for the potential inhibitors.Chapter Three:This chapter gives the experimental tests of the biological activity of all21potential compounds. The tests include the cytotoxity, cell cycle effects and enzyme inhibition. Finally, six compounds were identified as the novel inhibitors for Cdc25A.Chapter Four:This chapter focus on the identification of binding mode between inhibitor NSC663284and Cdc25phosphates B. Molecular dynamics study was conducted started with the binding modes obtained by molecular docking experiments. One binding site was identified and its stability and mechanism was analysized. Two possible binding modes were also proposed through statistical analysis of the trajectories.Chapter Five:Interactions between drugs and Human serum albumin, base probes and DNA double helix, surfactants and bovine serum albumin were studied using experimental measurements and molecular docking. Through the sampled studies in different systems, the benefit of combination of the theoretical analysis and the experimental results was discussed.Chapter Six:This chapter summarizes the whole work and gives a thought to the limitations. A simple outlook is also proposed for the future work.