The drug binding site of human α1-acid glycoprotein: Insight from induced circular dichroism and electronic absorption spectra

Zsila, Ferenc; Iwao, Yasunori

doi:10.1016/j.bbagen.2007.01.009

Cited by 90 publications

(66 citation statements)

References 55 publications

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“…HSA (100 lM) and AGP (5 lM) were used either together or separately in PAMPA. The ratio used between HSA and AGP was equivalent ($20:1) to that found in human plasma (Kratochwil et al, 2002;Zsila and Iwao, 2007). The concentration of HSA used in this assay is up to five times lower as encountered in the human body but this concentration was found suitable to obtain equilibrium dissociation (K d ) similar to that obtained with physiologically HSA concentration (Lazaro et al, 2008).…”

Section: Pampa In the Presence Of Proteinsmentioning

confidence: 82%

“…AGP (ca. 48 kDa and 183 aa (Fournier et al, 2000;Israili and Dayton, 2001)) is the second major plasma protein responsible for drug distribution and represents approximately 1-3% of the total plasma protein, with a concentration ranging from 10 to 30 lM in a healthy person (Zsila and Iwao, 2007). Due to its physicochemical properties, AGP preferentially binds basic compounds, but it can also bind acidic and neutral compounds (Israili and Dayton, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Modification of a PAMPA model to predict passive gastrointestinal absorption and plasma protein binding

Bujard

Voirol

Carrupt

et al. 2015

European Journal of Pharmaceutical Sciences

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Section: Pampa In the Presence Of Proteinsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Modification of a PAMPA model to predict passive gastrointestinal absorption and plasma protein binding

Bujard

Voirol

Carrupt

et al. 2015

European Journal of Pharmaceutical Sciences

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“…Serum proteins control the availability and the distribution of most drugs. HSA principally interacts with acidic molecules (7) like fusidic acid and novobiocin, while AGP is a major target for the binding of a wide variety of basic and neutral drugs (17). By binding to HSA, many hydrophobic drugs with low solubilities can be transported to reach their target tissues effectively.…”

Section: Discussionmentioning

confidence: 99%

Use of a Surface Plasmon Resonance Method To Investigate Antibiotic and Plasma Protein Interactions

Banères-Roquet

Gualtieri

Villain-Guillot

et al. 2009

Antimicrob Agents Chemother

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The pharmacologic effect of an antibiotic is directly related to its unbound concentration at the site of infection. Most commercial antibiotics have been selected in part for their low propensity to interact with serum proteins. These nonspecific interactions are classically evaluated by measuring the MIC in the presence of serum. As higher-throughput technologies tend to lose information, surface plasmon resonance (SPR) is emerging as an informative medium-throughput technology for hit validation. Here we show that SPR is a useful automatic tool for quantification of the interaction of model antibiotics with serum proteins and that it delivers precise real-time kinetic data on this critical parameter.Serum proteins play an important role in binding to many drugs, including antibiotics. In general, serum proteins decrease the free fraction of antibiotic available for the elimination of bacteria, since only the non-protein-bound molecules are pharmacologically active. The proteins involved in this sequestration are mainly human serum albumin (HSA), the most abundant serum protein (4% wt/vol); ␣-1-acid glycoprotein (AGP); and gamma globulin (5, 7, 11).Currently, most of the reports of the inhibitory effects of serum proteins on antibiotics are derived from in vitro studies that have employed the MIC method (3, 9) or time-killing curves (16). The findings described in those reports correlate well with in vivo data (13) and are useful for evaluation of the potential of a new drug candidate. However, it is also necessary to rapidly and precisely characterize how a molecule binds to serum proteins in terms of affinity constants to drive the synthesis of new and more efficient analogs. A variety of physical techniques for measurement of the levels of protein binding have been proposed. The most classical are ultracentrifugation (3) and dialysis (3,8); but other alternative techniques have been used, like circular dichroism analysis (1) and extrinsic fluorescence analysis (15). More recently, surface plasmon resonance (SPR) was proposed as a medium-to high-throughput alternative for evaluation of the kinetics of relatively lipophilic drugs that bind to human serum proteins in real time (14).Antibiotics are characterized as having a relatively high hydrophilicity compared to the hydrophilicities of other drug classes. Consequently, antibiotics have lower affinities for serum proteins. Because the development of fast analytical methods that allow the measurement of antibiotic-serum protein interaction kinetics with a small amount of sample is desirable, we have evaluated if SPR can measure low affinities and how SPR can be used to prescreen rapidly libraries of antibiotic candidates for their propensity to bind to serum proteins. MATERIALS AND METHODSBacterial strains, antimicrobial agents, and media. Staphylococcus aureus reference strain CIP 76.25 (ATCC 25923) was used. S. aureus was grown, subcultured, and quantified in Mueller-Hinton broth and on Mueller-Hinton agar (Difco Laboratories, Detroit, MI). Antimicrobial ag...

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“…Similarly to various AAG ligands having a rigid, planar ring system, the observed CD activity of 7 may be induced through non-degenerate exciton coupling with high-energy π-π * transitions of adjacent aromatic side chains of the binding pocket. 39,40 Sequential molecular docking of compound 4 to the A variant of AAG Computational docking calculation was also performed to obtain insight into the molecular details of the AAG association of compound 4. Taking into account the CD and UV spectroscopic results, two molecules of compound 4 were docked sequentially into the binding room of AAG.…”

Section: Hsa Binding Studies By Affinity Chromatographymentioning

confidence: 99%

Synthesis and serum protein binding of novel ring-substituted harmine derivatives

et al. 2015

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A series of new derivatives of the natural β-carboline alkaloid harmine, introducing hydrophobic substituents into positions 7 and 9 were synthetized as potential anticancer agents. Their binding affinities for human serum albumin (HSA) and α 1 -acid-glycoprotein (AAG) were investigated by affinity chromatography combined with fluorescence, circular dichroism (CD) and UV absorption spectroscopy. The weak binding of harmine to both proteins (K a ~ 3 × 10 4 M -1 ) was highly increased by aromatic substitutions (K a ~ 10 5 -10 6 M -1 ).Derivatives having a substituted benzyl group in the N 9 -position of the β-carboline nucleus showed about tenfold and hundred fold affinity enhancement for HSA and AAG, respectively.Such a strong plasma protein interaction would be of pharmacokinetic relevance for these potential drug candidates. Induced CD spectra indicated the variant selective, dimeric binding of the 7-pyridylethoxy derivative to AAG. Absorbance and fluorescence spectra refer to the binding preference of the neutral form of the studied β-carbolines for both proteins.

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The drug binding site of human α1-acid glycoprotein: Insight from induced circular dichroism and electronic absorption spectra

Cited by 90 publications

References 55 publications

Modification of a PAMPA model to predict passive gastrointestinal absorption and plasma protein binding

Modification of a PAMPA model to predict passive gastrointestinal absorption and plasma protein binding

Use of a Surface Plasmon Resonance Method To Investigate Antibiotic and Plasma Protein Interactions

Synthesis and serum protein binding of novel ring-substituted harmine derivatives

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