Insights into Ligand-Elicited Activation of Human Constitutive Androstane Receptor Based on Novel Agonists and Three-Dimensional Quantitative Structure−Activity Relationship

Jyrkkärinne, Johanna; Windshügel, Björn; Rönkkö, Toni; Tervo, Anu J.; Küblbeck, Jenni; Lahtela‐Kakkonen, Maija; Sippl, Wolfgang; Poso, Antti; Honkakoski, Paavo

doi:10.1021/jm800731b

Cited by 34 publications

(42 citation statements)

References 77 publications

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“…Additionally, all active phthalate esters except DEHP were extend into the most hydrophobic region of the pocket ( Figure 2B), and the chemicals are found to be away from the region of Leu343, which is thought to have a negative effect on the ability of ligands to bind human CAR. 30 Furthermore, they come to a similar position in the pocket, as the distances between amino acid residues are similar ( Figure S3). The U-shaped conformations of the phthalates upon binding are in good agreement with the conformation of CITCO in the human CAR crystal structure.…”

Section: Discussionmentioning

confidence: 82%

Structure-Dependent Activity of Phthalate Esters and Phthalate Monoesters Binding to Human Constitutive Androstane Receptor

Zou

Zhang

Nakanishi

et al. 2015

Chem. Res. Toxicol.

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The present study investigated the human constitutive androstane receptor (CAR) binding activities of 23 phthalate esters and 10 phthalate monoesters using a fast and sensitive human CAR yeast two-hybrid assay. Of 23 phthalate esters, 16 were evaluated as positive, and the 10% relative effective concentrations (REC10) ranged from 0.28 (BBP) to 29.51 μM (DEHP), whereas no obvious binding activities were found for the phthalate esters having alkyl chains more than six carbons in length. Of 10 phthalate monoesters, only monoethyl phthalate (MEP), monoisobutyl phthalate (MIBP), and mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) elicited human CAR binding activities. The REC10 values of MEP and MIBP were 4.27 and 14.13 μM, respectively, higher than those of their corresponding phthalate esters (1.45 μM for DEP and 0.83 μM for DIBP), whereas TBMEHP (0.66 μM) was much lower than TBHP (>10(2) μM). A molecular docking method was performed to simulate the interaction modes between phthalates and human CAR, and active phthalates were found to lie at almost the same site in the human CAR pocket. The docking results suggest that the strong binding of phthalates to human CAR arises primarily from hydrophobic interactions, π-π interactions, and steric effects and that weak hydrogen bonds and weak halogen bonds greatly contribute to the high binding activity of TBMEHP. In conclusion, the current study clarified that an extensive array of phthalates are activators of human CAR.

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Section: Discussionmentioning

confidence: 82%

Structure-Dependent Activity of Phthalate Esters and Phthalate Monoesters Binding to Human Constitutive Androstane Receptor

Zou

Zhang

Nakanishi

et al. 2015

Chem. Res. Toxicol.

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“…The pregnane X receptor (PXR) belongs to the NR1I family and regulates enzymes and transporters involved in xenobiotic detoxification as well as maintaining a homeostatic balance of endobiotics, including bile acids, cholesterols, and steroid hormones (Jyrkkärinne et al, 2008). PXR mediates activation of gene sets pertinent to xenobiotic metabolism, such as cytochrome 450 superfamily members CYP1, CYP2B, CYP2C, and CYP3A4 in rodents and humans (Maglich et al, 2002;Plant, 2007;di Masi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

Pan

Li²,

Gregory³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human pregnane X receptor (hPXR) plays a key role in regulating metabolism and clearance of endogenous and exogenous substances. Identification of novel hPXR activators among commercial drugs may aid in avoiding drug-drug interactions during coadministration. We applied ligand-based computational approaches for virtual screening of a commonly prescribed drug database (SCUT). Bayesian classification models were generated with a training set comprising 177 compounds using Fingerprints and 117 structural descriptors. A cell-based luciferase reporter assay was used for evaluation of chemical-mediated hPXR activation in HepG2 cells. All compounds were tested at 10 M concentration with rifampicin and dimethyl sulfoxide as positive and negative controls, respectively. The Bayesian models showed specificity and overall prediction accuracy up to 0.92 and 0.69 for test set compounds. Screening the SCUT database with this model retrieved 105 hits and 17 compounds from the top 25 hits were chosen for in vitro testing. The reporter assay confirmed that nine drugs, i.e., fluticasone, nimodipine, nisoldipine, beclomethasone, finasteride, flunisolide, megestrol, secobarbital, and aminoglutethimide, were previously unidentified hPXR activators. Thus, the present study demonstrates that novel hPXR activators can be efficiently identified among U.S. Food and Drug Administrationapproved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.

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“…However, CAR is unique, relative to other NRs, in its ability to maintain a constitutive activity in the absence of a bound ligand. This ability is also referred to as an indirect activation, the exact mechanism of which remains to be elucidated [325,326]. In its inactive form, CAR, just like PXR, is bound to heat shock protein 90 (Hsp90) in the cytoplasm [327].…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Enteric Microbiota–Gut–Brain Axis from the Perspective of Nuclear Receptors

Duszka

Wahli

2018

IJMS

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Nuclear receptors (NRs) play a key role in regulating virtually all body functions, thus maintaining a healthy operating body with all its complex systems. Recently, gut microbiota emerged as major factor contributing to the health of the whole organism. Enteric bacteria have multiple ways to influence their host and several of them involve communication with the brain. Mounting evidence of cooperation between gut flora and NRs is already available. However, the full potential of the microbiota interconnection with NRs remains to be uncovered. Herewith, we present the current state of knowledge on the multifaceted roles of NRs in the enteric microbiota–gut–brain axis.

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Insights into Ligand-Elicited Activation of Human Constitutive Androstane Receptor Based on Novel Agonists and Three-Dimensional Quantitative Structure−Activity Relationship

Cited by 34 publications

References 77 publications

Structure-Dependent Activity of Phthalate Esters and Phthalate Monoesters Binding to Human Constitutive Androstane Receptor

Structure-Dependent Activity of Phthalate Esters and Phthalate Monoesters Binding to Human Constitutive Androstane Receptor

Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

Enteric Microbiota–Gut–Brain Axis from the Perspective of Nuclear Receptors

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