Association of Valdecoxib, a Nonsteroidal Anti‐Inflammatory Drug, with Human Serum Albumin

Encinas, M. V.; Lissi, E. A.; Vergara, Claudio

doi:10.1111/php.12158

Cited by 2 publications

(2 citation statements)

References 43 publications

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“…In the light of the importance of the binding properties of HSA, much crystallographic and spectroscopic data on HSA:drug complexes has been reported in the literature, − and many efforts have been performed to correctly determine the number of binding sites. , Moreover, several studies in solution were focused on the stabilizing effect of ligand binding on the protein structure. − To highlight similar stabilizing effects, we recently reported a structural and spectroscopic combined study on the unfolding pathway of HSA binding ibuprofen (Ibu), a nonsteroidal anti-inflammatory drug . As an extension of this study, in this work, the urea-induced unfolding of HSA in complex with two drugs is reported.…”

Section: Introductionmentioning

confidence: 92%

Ibuprofen and Propofol Cobinding Effect on Human Serum Albumin Unfolding in Urea

et al. 2014

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The unfolding pathway of the defatted human serum albumin (HSA) binding ibuprofen and propofol has been studied by using small-angle X-ray scattering (SAXS) and the support of circular dichroism data. A set of HSA solutions with urea concentrations between 0.00 and 9.00 M was analyzed, and the singular value decomposition method applied to the complete SAXS data set allowed us to distinguish four different states in solution. Besides the native and unfolded forms, two intermediates I1 and I2 have been identified, and the low-resolution structures of these states were obtained by exploiting both ab initio and rigid body fitting methods. The I1 structure was characterized by only one open domain (domain I, which does not host a binding site for either of the ligands), whereas I2 presents only one closed domain (domain III). A direct comparison with the unfolding pathway of the HSA:Ibu complex (Galantini et al. Biophys. Chem. 2010, 147, 111-122) pointed out that the presence of propofol as a second ligand, located in subdomain IIIB, leads to the appearance of an intermediate with two closed domains (domains II and III), which are those that accommodate the ligands. Moreover, the equilibrium between I2 and the unfolded form is slightly shifted toward higher urea concentrations. These results suggest that the cobinding significantly hinders the unfolding process.

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Section: Introductionmentioning

confidence: 92%

Ibuprofen and Propofol Cobinding Effect on Human Serum Albumin Unfolding in Urea

et al. 2014

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“…These curves show negative deviation from linearity, mainly in the higher concentration range of indomethacin, and concave towards the x-axis. This phenomenon usually happens when there is more than one tryptophan residue with a distinct environment and different accessibility to the quencher [ 45 , 49 , 50 ], but it is well known that HSA has only one tryptophan residue located in the subdomain IIA, thus, there is a possibility of the existence of more than one binding site for indomethacin inside HSA [ 51 ], and the larger distance of secondary binding site in comparison to the primary one reduced the quenching efficiency, thus, a negative deviation in the Stern–Volmer plots could be expected [ 52 , 53 , 54 ]. Silva and coworkers have suggested that the binding of a ligand to the HSA may lead to the possible conformational change followed by the exposition of lower affinity binding sites [ 55 ].…”

Section: Resultsmentioning

confidence: 99%

Detailed Experimental and In Silico Investigation of Indomethacin Binding with Human Serum Albumin Considering Primary and Secondary Binding Sites

et al. 2023

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The interaction of indomethacin with human serum albumin (HSA) has been studied here considering the primary and secondary binding sites. The Stern–Volmer plots were linear in the lower concentration range of indomethacin while a downward curvature was observed in the higher concentration range, suggesting the presence of more than one binding site for indomethacin inside HSA due to which the microenvironment of the fluorophore changed slightly and some of its fraction was not accessible to the quencher. The Stern–Volmer quenching constants (KSV) for the primary and secondary sites were calculated from the two linear portions of the Stern–Volmer plots. There was around a two-fold decrease in the quenching constants for the low-affinity site as compared to the primary binding site. The interaction takes place via a static quenching mechanism and the KSV decreases at both primary and secondary sites upon increasing the temperature. The binding constants were also evaluated, which show strong binding at the primary site and fair binding at the secondary site. The binding was thermodynamically favorable with the liberation of heat and the ordering of the system. In principle, hydrogen bonding and Van der Waals forces were involved in the binding at the primary site while the low-affinity site interacted through hydrophobic forces only. The competitive binding was also evaluated using warfarin, ibuprofen, hemin, and a warfarin + hemin combination as site markers. The binding profile remained unchanged in the presence of ibuprofen, whereas it decreased in the presence of both warfarin and hemin with a straight line in the Stern–Volmer plots. The reduction in the binding was at a maximum when both warfarin and hemin were present simultaneously with the downward curvature in the Stern–Volmer plots at higher concentrations of indomethacin. The secondary structure of HSA also changes slightly in the presence of higher concentrations of indomethacin. Molecular dynamics simulations were performed at the primary and secondary binding sites of HSA which are drug site 1 (located in the subdomain IIA of the protein) and the hemin binding site (located in subdomain IB), respectively. From the results obtained from molecular docking and MD simulation, the indomethacin molecule showed more binding affinity towards drug site 1 followed by the other two sites.

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Association of Valdecoxib, a Nonsteroidal Anti‐Inflammatory Drug, with Human Serum Albumin

Cited by 2 publications

References 43 publications

Ibuprofen and Propofol Cobinding Effect on Human Serum Albumin Unfolding in Urea

Ibuprofen and Propofol Cobinding Effect on Human Serum Albumin Unfolding in Urea

Detailed Experimental and In Silico Investigation of Indomethacin Binding with Human Serum Albumin Considering Primary and Secondary Binding Sites

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