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Investigation by Fluorescence Spectroscopy, Resonance Rayleigh Scattering and Zeta Potential Approaches of the Separate and Simultaneous Binding Effect of Paclitaxel and Estradiol with Human Serum Albumin

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Abstract:

Separate and simultaneous binding effects of paclitaxel (a drug with anti-tumor activity) and estradiol (used for treating multiple maladies) with human serum albumin (HSA) were investigated by fluorescence quenching, UV absorption, circular dichroism, zeta potential and molecular dynamic techniques. An extensive fluorescence quenching was observed during the reaction of drugs and HSA and was rationalized in terms of a static quenching mechanism. The molecular distances between the donor (HSA) and acceptors (paclitaxel or estradiol) in binary and ternary systems were estimated according to Forster's theory of dipole-dipole non-radiation energy transfer. The features of drug-induced structural disturbances of HSA have been studied in detail by synchronous fluorescence and circular dichroism (CD) analysis. The resonance Rayleigh scattering (RRS) intensities were proportional to the paclitaxel and estradiol concentrations in the range of respectively (0-8)×10-6 and (0-1)×10-4 mM in binary systems. The critical induced aggregation concentrations (CCIAC) of paclitaxel and estradiol for binary and ternary systems were determined by nonlinear relationships between the enhancement of the RRS intensities and the drug concentrations. A comparison between binary and ternary systems for two drugs allowed us to estimate the effect of a drug on the initial formation aggregation of the second drug. The zeta potential results were used to verify the existence of complexation and confirmed the CCIAC values obtained by the RRS technique. This phenomenon was supported by a progressive rise of the protein charge to a reversal point as a consequence of drug binding. The quantitative analysis data of circular dichroism (CD) spectra demonstrated that the binding of paclitaxel and/or estradiol to HSA induced conformational changes in HSA. Moreover, the α-helix content in HSA greatly decreased in the presence of paclitaxel as opposed when estradiol was present. Protein-ligand docking suggested that estradiol bound to residues situated in subdomain IIA of HSA. On the other hand, in the ternary system, the presence of the first drug decreased the binding affinity of the second drug to HSA. Therefore binding effects of paclitaxel and estradiol with HSA alone have different behavior than simultaneous interaction.





Keywords: CCIAC values; CD; Circular dichroism spectra; Gasteiger charges; HAS; Molecular modeling; RRS; Rayleigh scattering; Stern-Volmer constant; X-ray crystallography; electrostatic interactions; estradiol; fluorescence emission spectra; fluorescence quenching; fluorophore; hydrophobic cavities; hydrophobic interactions; molecular dynamics; multi-drug therapy; paclitaxel; quenching; zeta potential

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986611796011473

Publication date: September 1, 2011

More about this publication?
  • Protein & Peptide Letters publishes short papers in all important aspects of protein and peptide research, including structural studies, recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, drug design etc. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallisation, and preliminary structure determinations of biologically important proteins are acceptable. Purely theoretical papers are also acceptable provided they provide new insight into the principles of protein/peptide structure and function.
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