QSAR model for human pregnane X receptor (PXR) binding: screening of environmental chemicals and correlations with genotoxicity, endocrine disruption and teratogenicity
| Autor: | Jay Russell Niemelä, Marianne Dybdahl, Svava Ósk Jónsdóttir, Nikolai Georgiev Nikolov, Eva Bay Wedebye |
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| Rok vydání: | 2012 |
| Předmět: |
Quantitative structure–activity relationship
Receptors Steroid Estrogen receptor Quantitative Structure-Activity Relationship Pharmacology Toxicology medicine.disease_cause Ligands digestive system Sensitivity and Specificity Molecular descriptor Toxicity Tests medicine Humans Clotrimazole Receptor Pregnane X receptor Felodipine Chemistry Mutagenicity Tests Ligand binding assay Pregnane X Receptor Reproducibility of Results digestive system diseases Androgen receptor Teratogens Biochemistry Genotoxicity |
| Zdroj: | Toxicology and applied pharmacology. 262(3) |
| ISSN: | 1096-0333 |
| Popis: | The pregnane X receptor (PXR) has a key role in regulating the metabolism and transport of structurally diverse endogenous and exogenous compounds. Activation of PXR has the potential to initiate adverse effects, causing drug-drug interactions, and perturbing normal physiological functions. Therefore, identification of PXR ligands would be valuable information for pharmaceutical and toxicological research. In the present study, we developed a quantitative structure-activity relationship (QSAR) model for the identification of PXR ligands using data based on a human PXR binding assay. A total of 631 molecules, representing a variety of chemical structures, constituted the training set of the model. Cross-validation of the model showed a sensitivity of 82%, a specificity of 85%, and a concordance of 84%. The developed model provided knowledge about molecular descriptors that may influence the binding of molecules to PXR. The model was used to screen a large inventory of environmental chemicals, of which 47% was found to be within domain of the model. Approximately 35% of the chemicals within domain were predicted to be PXR ligands. The predicted PXR ligands were found to be overrepresented among chemicals predicted to cause adverse effects, such as genotoxicity, teratogenicity, estrogen receptor activation and androgen receptor antagonism compared to chemicals not causing these effects. The developed model may be useful as a tool for predicting potential PXR ligands and for providing mechanistic information of toxic effects of chemicals. |
| Databáze: | OpenAIRE |
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