The Studies Of Interaction Between Sorafenib And Biological Macromolecules

In this article, many spectroscopies, including UV-visible spectroscopy, fluorescence spectroscopy and circular dichroism, were used to study the interaction between anticancer drug sorafenib and macromolecule, and molecular simulation was used to explain the binding process in micro-level respect. The research has mainly focused on the following four chapters,In the first part, we provided a brief introduction about the structure and function of macromolecule (BSA, DNA) and the research progress of anticancer drug sorafenib. The methods which are used to study on the interaction between small moleculars and biomacromolecules have also been introduced briefly. In the end of the chapter, the research significance for the study of interaction of sorafenib and biomacromolecules was pointed out.In the second part, The binding interaction of sorafenib with calf thymus DNA (ct-DNA) was studied by UV-vis absorption spectroscopy, fluorescence emission spectroscopy, circular dichroism (CD), viscosity measurement and molecular docking methods. The experimental results revealed that there was obviously the binding interaction between sorafenib and ct-DNA. The binding constant (Kb) of sorafenib with ct-DNA was5.6×103M-1at298K. The enthapic(enthalpy) and entropic(entropy) changes (ΔH0and ΔS0) in the binding process of sorafenib with ct-DNA were-27.66KJ mol-1and-21.02J mol-1K-1, respectively, indicating that the main binding interaction forces are Van der Waals force and hydrogen bonding force. The docking results suggested that sorafenib prefers to bind on the minor groove of A-T rich DNA and the binding site of sorafenib is4base pairs long. In the sorafenib-DNA complex, the conformation change of sorafenib was obviously observed and the change was close relation to the structure of DNA, implying that the flexibility of sorafenib molecule plays (an) important role in the formation of the stable sorafenib-ct-DNA complex.In the third chapter, an attempt has been made to study the binding of sorafenib to bovine serum albumin (BSA) using fluorescence spectroscopy, circular dichrosim (CD) and molecular simulation methods. The results revealed that there was a static quenching of BSA induced by sorafenib due to the formation of sorafenib-BSA complex, the binding constant and number of binding site for binding process were measured under simulated physiological condition (pH=7.4), which were6.8×104L mol-1and1at310K, respectively. Based on thermodynamic parameter analysis, the negative value of ΔG0suggested the binding process of sorafenib and BSA is spontaneous, the values of ΔH0and ΔS0were-72.15kJ mol-1and-140.35J mol-1K-1, respectively, which indicated that the main interaction forces of sorafenib with BSA were van der Waals force and hydrogen bonding interaction. And, the results was proved by molecular docking. From the results of site marker competitive experiments and molecular docking, it can be deduced that sorafenib binds to the subdomain IIA (site I) of BSA and leads to a slight change of the conformation of BSA, the conformation of sorafenib also changes to increase the stability of the sorafenib-BSA system.In the fourth chapter, it was summarized the binding process between sorafenib with BSA and ct-DNA, and the future direction of this work was also pointed out in the end.