Study Of Interaction Between The Nucleobase-modified Nucleoside And Serum Albumin

Nucleosides and their derivatives exhibit significant biological activities such as antitumor, antiviral and antibacterial activities. They are a sort of important drugs and pharmaceutic intermediates. It is recognized that nucleosides have the most potential function to restrain virus. Drug activity could be greatly enhanced when the natural nucleoside have been modified and embellished, thus, the study in this field has become a focus in modern medicinal chemistry, molecular biology and medicament subject in recent years.Serum albumin, the most abundant protein constituent of blood plasma and serves as a protein storage component, has many important physiological functions. Serum albumin can interact with many endogenous and exogenous substances including many drugs. It is important to study the interaction of drug with the protein because protein-drug binding plays an important role in pharmacology and pharmacodynamics. the study of interaction mechanism between small molecules and protein have very important significance for the pharmacokinetic behavior and the exploitations of new drugs. Establishing the binding model of the drug with serum albumin and investigating the binding mechanism, binding constants, binding sites, binding mode and binding distance, is significant to reveal Pharmacokinetics problems and guide for design and exploit new drugs. The significance of interaction between drugs and serum albumin in the pharmacokinetics and clinical pharmacology lead the study of this aspect to an active study field.In this dissertation, fluorescence quenching method in combination with UV and molecular modeling were firstly used to investigate the interaction of seven nucleobase-modified nucleosides with serum albumin under simulated physiological conditions (pH 7.40, ionic strength 0.10 mol/L), they are 5-Iodo-deoxyuridine (IDUR), 5-iodouridine (5-IUR), 6-Mercaptopurine (6-MP), Thioguanine (6-TG), Cyanogen-ethylic-5-chlorinuracil uracil (CECU), Cyanogen-ethylic uracil (CEU), 5-Iodouracil (5-IU) . This dissertation consists of seven chapters.Chapter 1: In this chapter, the function of nucleobase-modified nucleoside, the structures, properties and functions of proteins were briefly introduced. The principle and methods of fluorescence techniques and molecular modeling for study the interaction of small molecules with proteins were described. Chapter 2: Under the simulated physiological conditions, the interactions were investigated between the seven nucleobase-modified nucleosides and serum albumin utilizing fluorescence quenching method in combination with UV spectrum. The quenching mechanisms of nucleobase-modified nucleosides to serum albumin were determined and the quenching constants at different temperatures were calculated.Chapter 3: On the basis of interaction mechanism, the binding constants at the different temperatures were calculated between the seven nucleobase-modified nucleosides and serum albumin by using Lineweaver-Burk equation. The partial thermodynamic parameters were obtained according to thermodynamic equations, and the main acting forces were determined.Chapter 4: According to the F?rster energy transfer theory and the integral of the overlap spectra between the fluorescence spectra of serum albumin and the ultra-visible absorption spectra of the nucleobase-modified nucleoside, the binding distances between nucleobase-modified nucleoside and tryptophan residue of serum albumin were calculated.Chapter 5: Based on the data and the results of spectroscopic study, the interaction between nucleobase-modified nucleoside and human serum albumin were studied by using molecular modeling technique. The molecular modeling between nucleobase-modified nucleosides and serum albumin were established.Chapter 6: The effect of common ions on binding constants was discussed. The results indicated that the binding constants between nucleobase-modified nucleosides and serum albumin were changed in the presence of common ions.Chapter 7: The main innovations of this paper were summarized, and the prospects were suggested.