NMR in Pharmacokinetic and Pharmacodynamic Profiling

Sun, Chaohong; Huth, Jeffrey R.; Hajduk, Philip J.

doi:10.1002/cbic.200500028

Cited by 11 publications

(6 citation statements)

References 74 publications

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“…20 In the subdomains IIA and IIIA, the specific drug binding sites-the warfarin site and the diazepam site-are located. [24][25][26][27][28] These binding sites are the binding areas for small heterocyclic or aromatic carboxylic acids. Generally, the size of the ligand and drug-BSA interactions and dye-BSA interactions is influenced by the chemical structure of the respective compounds or species (steric effects) as well as their charge and hydrophilicity, which are closely related.…”

Section: Discussionmentioning

confidence: 99%

Controlled Modulation of Serum Protein Binding and Biodistribution of Asymmetric Cyanine Dyes by Variation of the Number of Sulfonate Groups

Hamann

Brehm²,

Pauli³

et al. 2011

Mol Imaging

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To assess the suitability of asymmetric cyanine dyes for in vivo fluoro-optical molecular imaging, a comprehensive study on the influence of the number of negatively charged sulfonate groups governing the hydrophilicity of the DY-67x family of asymmetric cyanines was performed. Special attention was devoted to the plasma protein binding capacity and related pharmacokinetic properties. Four members of the DY-67x cyanine family composed of the same main chromophore, but substituted with a sequentially increasing number of sulfonate groups (n = 1-4; DY-675, DY-676, DY-677, DY-678, respectively), were incubated with plasma proteins dissolved in phosphate-buffered saline. Protein binding was assessed by absorption spectroscopy, gel electrophoresis, ultrafiltration, and dialysis. Distribution of dye in organs was studied by intraveneous injection of 62 nmol dye/kg body weight into mice (n = 12; up to 180 minutes postinjection) using whole-body near-infrared fluorescence imaging. Spectroscopic studies, gel electrophoresis, and dialysis demonstrated reduced protein binding with increasing number of sulfonate groups. The bovine serum albumin binding constant of the most hydrophobic dye, DY-675, is 18 times higher than that of the most hydrophilic fluorophore, DY-678. In vivo biodistribution analysis underlined a considerable influence of dye hydrophilicity on biodistribution and excretion pathways, with the more hydrophobic dyes, DY-675 and DY-676, accumulating in the liver, followed by strong fluorescence signals in bile and gut owing to accumulation in feces and comparatively hydrophilic DY-678-COOH accumulating in the bladder. Our results demonstrate the possibility of selectively controlling dye-protein interactions and, thus, biodistribution and excretion pathways via proper choice of the fluorophore's substitution pattern. This underlines the importance of structure-property relationships for fluorescent labels. Moreover, our data could provide the basis for the rationalization of future contrast agent developments.

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Section: Discussionmentioning

confidence: 99%

Controlled Modulation of Serum Protein Binding and Biodistribution of Asymmetric Cyanine Dyes by Variation of the Number of Sulfonate Groups

Hamann

Brehm²,

Pauli³

et al. 2011

Mol Imaging

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“…P450-metabolizing enzymes are responsible for drug−drug interactions common to a significant number of drugs (). While the structural details for P450 inhibition are still under investigation , it is known that electrophilic compounds do inhibit this class of enzymes. This may involve electrophilic attack of the heme or the heme-coordinating cysteine to disrupt xenobiotic oxidation.…”

Section: Resultsmentioning

confidence: 99%

“…For these reasons, batteries of in vitro tests have been developed that correlate with a toxicological outcome but are rapid and cost-effective enough to enable the evaluation of hundreds or even thousands of compounds. Most of these in vitro tests attempt to assess the impact of a drug on particular proteins or biological pathways associated with toxicity [e.g., hERG channel binding , inhibition or induction of P450 enzymes , or mutagenicity ].…”

Section: Introductionmentioning

confidence: 99%

Toxicological Evaluation of Thiol-Reactive Compounds Identified Using a La Assay To Detect Reactive Molecules by Nuclear Magnetic Resonance

Huth

Song

Mendoza

et al. 2007

Chem. Res. Toxicol.

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We have recently reported on the development of a La assay to detect reactive molecules by nuclear magnetic resonance (ALARM NMR) to detect reactive false positive hits from high-throughput screening, in which we observed a surprisingly large number of compounds that can oxidize or form covalent adducts with protein thiols groups. In the vast majority of these cases, the covalent interactions are largely nonspecific (e.g., affect many protein targets) and therefore unsuitable for drug development. However, certain thiol-reactive species do appear to inhibit the target of interest in a specific manner. The question then arises as to the potential toxicology risks of developing a drug that can react with protein thiol groups. Here, we report on the evaluation of a large set of ALARM-reactive and -nonreactive compounds against a panel of additional proteins (aldehyde dehydrogenase, superoxide dismutase, and three cytochrome P450 enzymes). It was observed that ALARM-reactive compounds have significantly increased risks of interacting with one or more of these enzymes in vitro. Thus, ALARM NMR seems to be a sensitive tool to rapidly identify compounds with an enhanced risk of producing side effects in humans, including alcohol intolerance, the formation of reactive oxygen species, and drug-drug interactions. In conjunction with other toxicology assays, ALARM NMR should be a valuable tool for prioritizing compounds for lead optimization and animal testing.

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“…Compared to ITC, NMR gives a broader view of the dynamic of bindings at equilibrium and whether the interaction occurs on specific sites or solely causes HSA conformational changes without being attached [ 32 , 57 ]. In its infancy for studying PBUT interactions with proteins, 2-D NMR monitors all binding sites on the protein and quantitatively measures site-specific binding constants [ 58 , 59 ]. So far, only Li et al [ 32 ] have utilized this technique to identify potential secondary and tertiary structure changes in HSA while interacting with PBUTs using STD (saturated transfer difference) NMR to detect the intensity of bindings through an on-and-off induced magnetic field without affecting the unbonded toxins.…”

Section: Experimental Techniques Commonly Employedmentioning

confidence: 99%

Detailing Protein-Bound Uremic Toxin Interaction Mechanisms with Human Serum Albumin in the Pursuit of Designing Competitive Binders

Niestanak

Unsworth

2023

IJMS

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Chronic kidney disease is the gradual progression of kidney dysfunction and involves numerous co-morbidities, one of the leading causes of mortality. One of the primary complications of kidney dysfunction is the accumulation of toxins in the bloodstream, particularly protein-bound uremic toxins (PBUTs), which have a high affinity for plasma proteins. The buildup of PBUTs in the blood reduces the effectiveness of conventional treatments, such as hemodialysis. Moreover, PBUTs can bind to blood plasma proteins, such as human serum albumin, alter their conformational structure, block binding sites for other valuable endogenous or exogenous substances, and exacerbate the co-existing medical conditions associated with kidney disease. The inadequacy of hemodialysis in clearing PBUTs underscores the significance of researching the binding mechanisms of these toxins with blood proteins, with a critical analysis of the methods used to obtain this information. Here, we gathered the available data on the binding of indoxyl sulfate, p-cresyl sulfate, indole 3-acetic acid, hippuric acid, 3-carboxyl-4-methyl-5-propyl-2-furan propanoic acid, and phenylacetic acid to human serum albumin and reviewed the common techniques used to investigate the thermodynamics and structure of the PBUT–albumin interaction. These findings can be critical in investigating molecules that can displace toxins on HSA and improve their clearance by standard dialysis or designing adsorbents with greater affinity for PBUTs than HSA.

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NMR in Pharmacokinetic and Pharmacodynamic Profiling

Cited by 11 publications

References 74 publications

Controlled Modulation of Serum Protein Binding and Biodistribution of Asymmetric Cyanine Dyes by Variation of the Number of Sulfonate Groups

Controlled Modulation of Serum Protein Binding and Biodistribution of Asymmetric Cyanine Dyes by Variation of the Number of Sulfonate Groups

Toxicological Evaluation of Thiol-Reactive Compounds Identified Using a La Assay To Detect Reactive Molecules by Nuclear Magnetic Resonance

Detailing Protein-Bound Uremic Toxin Interaction Mechanisms with Human Serum Albumin in the Pursuit of Designing Competitive Binders

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