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Structural determinants of flavonoid binding to human serum albumin

Flavonoids are widely distributed secondary plant metabolites. They are found in everyday diet (fruits and vegetables) and numerous medicinal plants. After absorption, in humans, flavonoids bind to human serum albumin (HSA), the most abundant carrier blood protein. Binding of flavonoids to HSA may impact distribution and the free blood concentration of various drugs and hormones. The objective of this work was to determine structural features of flavonoids relevant for binding to HSA. Binding constants were determined experimentally by measuring steady-state fluorescence spectra of increasing flavonoid concentrations (0-10 µM) to HSA (1 µM). Molecular descriptors calculations were based on density functional theory ; the Gaussian09 program was used for quantum chemical calculations. These results were then integrated using Statistica 7.0 to elucidate structure- affinity relationship. In general, flavanones (0.5-2.2 x 104 M-1) have shown the lowest binding constants, followed by isoflavones (2.1- 4.9 x 104 M-1), while flavones (1.3-8.9 x 104 M- 1) and flavonols (1.2-7.4 x 104 M-1) are characterized by the highest binding constants. Most of the binding constants are in accordance with data from previously published studies, with a few exceptions, while for a few flavonoids literature data could not be found. At physiological pH analyzed flavonoids have a tendency to bind to the IIA binding site of HSA in the form of an anion. There are several key flavonoid properties that are associated with the respective binding affinity: (1) C3 nucleophilicity – enables classification of flavonoids into subclasses ; (2) O4 partial charge has shown strong association with the HSA binding affinity, reflecting its good hydrogen acceptor properties ; (3) R4 electrophilicity – lower electrophilicity is associated with higher affinity for HSA ; (4) high HOMO and LUMO energies reflect tighter binding ; and (5) coplanarity of both AC and B rings and A and C rings are associated with higher binding constants. Contrary to previously published results, this study shows that neither conjugation of B and AC rings nor hydrogen acceptor and donor properties of the B ring are common determinants of flavonoid binding to HSA. This study represents the most extensive study of flavonoids binding to HSA, complementing an experimental technique of fluorescence spectrophotometry with results of quantum mechanics approach to provide explanations of flavonoid binding properties. However, it is important to emphasize that all of the calculations were done in vacuo and laboratory measurements were done in vitro. Further studies are needed to evaluate biological implications of the described phenomenon like flavonoid-drug and flavonoid- hormone interactions.

disposition ; drug interaction ; herbal medicine ; active compounds

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