Journal article
Evaluation of Computational Docking to Identify Pregnane X Receptor Agonists in the ToxCast Database
Environmental health perspectives, Vol.118(10), pp.1412-1417
2010
DOI: 10.1289/ehp.1001930
PMCID: PMC2957921
PMID: 20558333
Abstract
Background: The pregnane X receptor (PXR) is a key transcriptional regulator of many genes [e.g., cytochrome P450s (CYP2C9, CYP3A4, CYP2B6), MDR1] involved in xenobiotic metabolism and excretion.
Objectives: As part of an evaluation of different approaches to predict compound affinity for nuclear hormone receptors, we used the molecular docking program GOLD and a hybrid scoring scheme based on similarity weighted GoldScores to predict potential PXR agonists in the ToxCast database of pesticides and other industrial chemicals. We present some of the limitations of different in vitro systems, as well as docking and ligand-based computational models.
Methods: Each ToxCast compound was docked into the five published crystallographic structures of human PXR (hPXR), and 15 compounds were selected based on their consensus docking scores for testing. In addition, we used a Bayesian model to classify the ToxCast compounds into PXR agonists and nonagonists. hPXR activation was determined by luciferase-based reporter assays in the HepG2 and DPX-2 human liver cell lines.
Results: We tested 11 compounds, of which 6 were strong agonists and 2 had weak agonist activity. Docking results of additional compounds were compared with data reported in the literature. The prediction sensitivity of PXR agonists in our sample ToxCast data set (n = 28) using docking and the GoldScore was higher than with the hybrid score at 66.7%. The prediction sensitivity for PXR agonists using GoldScore for the entire ToxCast data set (n = 308) compared with data from the NIH (National Institutes of Health) Chemical Genomics Center data was 73.8%.
Conclusions: Docking and the GoldScore may be useful for prioritizing large data sets prior to in vitro testing with good sensitivity across the sample and entire ToxCast data set for hPXR agonists.
Details
- Title: Subtitle
- Evaluation of Computational Docking to Identify Pregnane X Receptor Agonists in the ToxCast Database
- Creators
- Sandhya KORTAGERE - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United StatesMatthew D KRASOWSKI - Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United StatesErica J RESCHLY - Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United StatesMadhukumar VENKATESH - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, United StatesSridhar MANI - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, United StatesSean EKINS - Collaborations in Chemistry, Jenkintown, Pennsylvania, United States
- Resource Type
- Journal article
- Publication Details
- Environmental health perspectives, Vol.118(10), pp.1412-1417
- Publisher
- US Department of Health and Human Services; Research Triangle Park, NC
- DOI
- 10.1289/ehp.1001930
- PMID
- 20558333
- PMCID
- PMC2957921
- ISSN
- 0091-6765
- eISSN
- 1552-9924
- Language
- English
- Date published
- 2010
- Academic Unit
- Pathology
- Record Identifier
- 9984046801102771
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