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An in vitro and in silico investigation of human pregnane X receptor agonistic activity of poly- and perfluorinated compounds using the heuristic method–best subset and comparative similarity indices analysis
- Source :
- Chemosphere. 240:124789
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Poly- and perfluorinated compounds (PFCs) may induce potential endocrine-disrupting hormonal effects. However, the molecular mechanism of the toxicology of PFCs remains unclear, and the insufficient information is available on the biological activities of PFCs at present. In this study, the cell-based reporter gene assays were used to determine the agonistic activity of PFCs on the human pregnane X receptor (hPXR). The heuristic method combined with best subset modeling (HM-BSM) based on Dragon descriptors and comparative similarity indices analysis (CoMSIA) were employed to build classical quantitative structure-activity relationship (QSAR) and three-dimensional QSAR models, respectively. The applicability domain (AD) of the classical QSAR model was assessed. Both the HM-BSM and CoMSIA approaches demonstrated good robustness, predictive ability, and mechanistic interpretability. The r2 and leave-one-out cross-validation squared correlated coefficient (q2LOO) values were 0.872 and 0.759 for the HM-BSM, and 0.976 and 0.751 for the CoMSIA model, respectively. The hPXR agonistic activity of the PFCs predicted by the built HM-BSM and CoMSIA agreed well with experimental activity, with root mean square error (RMSE) values of 0.0803 and 0.117, respectively, and external validation squared correlated coefficients (q2EXT) of 0.972 and 0.932, respectively. The hPXR agonistic activity of PFCs was related to their molecular polarizability, charge and atomic mass. Hydrogen bonding and hydrophobic interactions constituted the primary intermolecular forces between PFCs and the hPXR. The developed models were used to screen the PFCs with high hPXR agonistic activity.
- Subjects :
- Quantitative structure–activity relationship
Environmental Engineering
Health, Toxicology and Mutagenesis
In silico
0208 environmental biotechnology
Quantitative Structure-Activity Relationship
02 engineering and technology
Computational biology
010501 environmental sciences
01 natural sciences
Similarity (network science)
Agonistic behaviour
Heuristics
Humans
Environmental Chemistry
Computer Simulation
0105 earth and related environmental sciences
Fluorocarbons
Pregnane X receptor
Chemistry
Pregnane X Receptor
Public Health, Environmental and Occupational Health
External validation
Hydrogen Bonding
General Medicine
General Chemistry
Pollution
In vitro
020801 environmental engineering
Hydrophobic and Hydrophilic Interactions
Applicability domain
Subjects
Details
- ISSN :
- 00456535
- Volume :
- 240
- Database :
- OpenAIRE
- Journal :
- Chemosphere
- Accession number :
- edsair.doi.dedup.....12e30b3a3e23514e34516341807082c9