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The Interaction of Clozapine and Aristolochic Acid I with Human Serum Albumin

Author: WuXinHu
Tutor: Jin
School: Lanzhou University
Course: Organic Chemistry
Keywords: Clozapine Aristolochic acidⅠ HSA Fluorescence spectroscopy CD Binding constant Binding site
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 55
Quote: 1
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Abstract


Human serum albumin (HSA) is the most abundant protein in plasma and constitutes approximately half of the protein found in human blood. HSA plays an important role in the transport and disposition of endogenous and exogenous ligands present in blood. Its surprising capacity to reversibly bind a large variety of drugs results in its prevailing role in drug pharmacokinetics and pharmacodynamics. In addition, the investigation of the interaction of HSA with drugs contributes to understand disposition, transportation, metabolism and efficacy of drugs. Clozapine (CLZ), an atypical antipsychotic drugs, is effective in treatment of schizophrenia. Aristolochic acid (AA)-containing herbs have been used as medicine in obstetrics and in the treatment of snake bites. The plant extracts have also been used for the therapy of arthritis, gout, rheumatism, and festering wounds. In this paper, on the basis of the previous research, the following major innovative works were carried out:1. The interaction of drugs (CLZ and AAⅠ) with HSA under simulative physiological conditions were studied using fluorescence spectra, UV-Vis absorption spectra, circular dichroism spectra and molecular docking methods. The results from every method was in good agreement.2. The fluorescence quenching mechanism, binding constants and the number of binding sites involving in the interaction of CLZ and AA I with HSA were investigated by Stern-volmer equation and van’t Hoff equation. At the same time, the thermodynamic parameters were calculated and the interaction forces were discussed.3. Time-resolved fluorescence spectroscopy and Resonance energy transfer theory were used to study the non-radiative energy transfer between Trp214 and drugs, and calculated the binding distance between them.4. Fluorescence spectra、competitive replacement experiments and molecular docking methods were used to study the binding sites of drugs in HSA.5. The effects of the two drugs on the secondary structure of HSA were investigated with CD techniques.The paper including three sections below:Chapter 1:The structure, functions and properties of protein studied were introduced briefly; The methods and actuality about the research of the interaction between small molecular drugs and protein were summarized.Chapter 2:The interaction of CLZ with human serum albumin (HSA) has been studied using fluorescence spectroscopy, UV-Vis spectra, CD spectroscopy, competitive replacement experiments and molecular docking methods under simulative physiological conditions. The results of spectroscopic measurements indicated that the intrinsic fluorescence of HSA was quenched by CLZ through static quenching mechanism and non-radiative energy transfer between Trp214 and CLZ. The specific binding of CLZ in the vicinity of SubdomainⅡA of HSA has been clarified. The binding constants and the numbers of binding site of CLZ with HSA were obtained from the fluorescence spectroscopy at different temperature, and the mainly intermolecular force were gained from thermodynamic parameters. The binding distance between CLZ and HSA was calculated from FRET theory. The effects of CLZ on HSA secondary structure were investigated by CD spectroscopy. Molecular docking studies indicated that the binding site of CLZ was located in SubdomainⅡA of HSA, which was consistence with the experiment results.Chapter 3:The binding of AAⅠwith HSA has been investigated by fluorescence spectroscopy, CD spectroscopy, competitive replacement experiments and molecular docking methods under simulative physiological conditions. The studied results suggested that the intrinsic fluorescence of HSA was quenched by AAⅠthrough static quenching mechanism and non-radiative energy transfer between AAⅠand Trp214. The specific binding of AAⅠin the vicinity of SubdomainⅡA (Sudlow’s siteⅠ) of HSA has been clarified. The binding constants and the numbers of binding site were obtained from the fluorescence spectroscopy. The binding distance between AAⅠand HSA was calculated from FRET theory. The effects of AAⅠon HSA secondary structure were investigated by CD spectroscopy. Molecular docking studies revealed that AAⅠwas binding at subdomainⅡA of HSA through multiple interactions, such as hydrophobic effect, van der Waals forces and hydrogen bonding.

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