On Investigations Between Small Molecule Drugs And Serum Albumins By Optical Spectroscopy And Molecular Computational Modeling

From structural and energetic aspects of these studies, research on interactions between purine analogues (Allopurinol (ALP), Acyclovir (ACV) and 8-Azaguanine (8-Azan) ) and serum albumin can help us to clarify the action mechanism of the drugs, such as drug metabolism, transportation and distribution, as well as protein conformational transformation, etc. This can provide a rational basis for the fundamental understanding of the interaction and achieve the development of therapeutic agents effectively. However, interaction between the three drugs and serum albumins has not been reported thus far. And due to the homological structure and comparability between bovine serum albumin (BSA) and human serum albumin (HSA), so it is of particular interest and improtance to explore this interaction between the drugs and serum albumins from the point of view of pharmacology and pharmacodynamics.The following major innovative works were carried out:(1) The unknown crystal structure of BSA was generated by homology modeling.(2) Experimental and computational simulation methods were combined to observe the interaction between drugs and serum albumins, and thus to compare the two experimental results (such as binding sites, protein conformational changes, etc.).(3) Small drugs and serum albumins, which have structural similarity, respectively, were chosen as research objects to investigate the difference between the interactions. This can help to know more detailed information about medicinal properties of drugs.This thesis can be divided into three parts as follows:Part 1: The interactions between allopurinol (ALP, which can inhibit the synthesis of uric acid) and serum albumins (BSA and HSA) in Tris-HCl buffer solutions at pH=7.40 were investigated by means of fluorescence, UV-Vis spectroscopy, combined with homology modeling and molecular docking. The three-dimensional structure of BSA was generated successfully by homology modeling. Molecular docking gives new insight into the interactions that ALP is located in a more hydrophobic environment in HSA than in BSA. Also, it indicates that the affinity of HSA is higher than that of BSA, and that hydrogen bonds increase the stability of the complexes.Part 2: By using fluorescence, UV-Vis spectroscopy, homology modeling and molecular docking, the interactions between the antiviral drug acyclovir (ACV) and bovine serum albumin (BSA) have been researched. Theoretical investigations based on homology modeling and molecular docking indicate that ACV is situated in a more hydrophilic environment in BSA, hydrogen bonds increases the stability of ACV-BSA complex, and that BSA has a high affinity for ACV.Part 3: The anti-cancer drug 8-Azaguanine (8-Azan) and bovine serum albumin (BSA) were chosen as research objects and have been investigated by means of fluorescence, UV-Vis spectroscopy, homology modeling and molecular docking. Theoretical investigations based on homology modeling and molecular docking suggests that the binding between 8-Azan and BSA is dominated by hydrophilic forces and hydrogen bonding. The theoretical investigations provide a good structural basis to explain the phenomenon of fluorescence quenching between 8-Azan and BSA.