Molecular Modeling Of Antharcycline Anticancer Drugs And Its Interaction With DNA

There are two sections in this thesis, one is the research on conformational space of the anthracycline anticancer drugs and their interaction with DNA, the other is the study of the electroosmotic drag of water in the proton exchange membrane. Anticancer drug research is significant to protect people's lives and health. Anthracycline antibiotics represent a major class of antitumor drugs which are widely used clinically for their high antitumor efficiency. But their clinical use is limited by dose-related serious cardiotoxic side effects. The cytotoxic mechanism of anthracyclines is extensively studied but not precisely understood and some of them are controversial. It will provide useful information for learning more about the cytotoxic mechanism through the detection of the conformational space and the interaction between the drugs and DNA at the atomic level. In this thesis, we used first principle calculations and molecular dynamics simulations to study the conformational space of the four anthracycline anticancer drugs (doxorubicin, daunorubicin, epirubicin, and idarubicin) widely used in clinical and the interaction between these drugs and DNA mediated by formaldehyde. The development and utilization of new energy is important to social sustainable development. Proton exchange membrane fuel cells (PEMFCs) have been developed extensively in recent years for their high energy conversion efficiency, simple structure, minimal environmental pollution, long life and so forth. Unfortunately, there are many technical barriers needing to be overcome for their large scale commercialization and civilian use. One of the technical barriers is the water management. To improve the understanding of the water management, it is important to study the electroosmotic drag of water in PEMFCs under external electric filed at atomic level. In this thesis, we also used molecular dynamics simulations to study the electroosmotic drag of water in hydrated potassium perfluorosulfonated polymer membrane under external electric filed. The main results of the two sections in our research are as follows:Section 1: The first principle calculation and the molecular dynamics simulation of anthracycline anticancer drugs(1) The conformational analysis of anthracycline anticancer drugs The conformational diversity of doxorubicin, daunorubicin, epirubicin, and idarubicin, is studied based on density functional theory calculations at the B3LYP/6-31G(d,p) level of theory. The calculations confirm three conformational domains: the anthracycline quinine-hydroquinone backbone, the anchor, and the daunosamine. The backbone exists in three conformations and three prototropic tautomerizations, the anchor in four conformations relating to the orientations of the C8 and C9 atoms, and the daunosamine also in four conformations according to the distance between the amino nitrogen and the quinine oxygen. The overall molecular conformation is determined by combination of the conformational types of all the three conformational domains. Finally, conformations of intercalated drug molecules reported in the literatures are classified according to these criteria.(2) The interaction analysis of aqueous solution of anthracycline anticancer drug-DNA adductThe four formaldehyde-mediated DNA-CH2-anthracycline adduct saline solution systems are studied by using a full atom molecular dynamics simulation. Drugs in these systems denote asâ… (adriamycin),â…¡(daunorubicin),â…¢(epirubicin) andâ… V (idarubicin), respectively. The conformations of the drug molecules, the hydrogen bond distribution within a drug and between drugs and DNA as well as the distribution of water around adducts are analyzed under the dynamics trajectories obtained from MD simulations. The results show that there exist two different conformations of drug inâ…¢andâ… V systems but only one inâ… andâ…¡systems.â… t is also shown that there are lots of hydrogen bond between drugs and DNA, but most of these are unstable. The conformations and hydrogen bond verify the existence of a virtual cross-linking structure and imply it's unstable at the same time. The relative stability isâ… V >â…¢>â… >â…¡in turn. The analysis of the water distribution around adduct shows that the strength of the interaction between drugs and DNA is enhanced with the help of the bridging water, and the relative intensity isâ… >â…¢>â…¡>â… V in order. These results indicate that the relative strength of the total interaction between drugs and DNA isâ…¢>â… V >â… >â…¡successively.Section 2: The molecular dynamics study of electroosmotic drag of water in hydrated potassium perfluorosulfonated polymer membrane1. The electroosmotic drag of water in hydrated potassium perfluorosulfonated polymer membrane in external electric fieldsThe electroosmotic drag and the corresponding mechanism of water molecules in hydrated potassium perfluorosulfonate electrolyte polymer membrane were studied using molecular dynamics simulations, and the relationship between the membrane structure and electroosmotic drag characteristics was analyzed. It is concluded that velocities of both H2O and K~+ obey the Maxwell velocity distribution function without external electric field applied. If an appropriate electric field is applied, the velocities of H2O and K~+ still obey the Maxwell velocity distribution in the direction perpendicular to the electric field, and obey the peak shifted Maxwell velocity distribution in the direction parallel to the electric field. The peak shifting velocities coincide with the average transport velocities of H2O and K~+ induced by the applied electric field, and could be applied to evaluate the electroosmotic drag coefficient of water. The results also show that the average number of water molecules in the first coordination shell of K~+ is 4.04, and the average transport velocity of these water molecules is about 57% of that of K~+. The electroosmotic drag coefficient contributed by these water molecules is about 77% of total the electroosmotic drag coefficient (2.97).