A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics.

Mekenyan, Ovanes G.; Veith, Gilman D.; Call, Daniel J.; Ankley, Gerald T.

doi:10.1289/ehp.961041302

Cited by 80 publications

(39 citation statements)

References 30 publications

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“…Overall, the ranking of toxic potencies of PCB congeners suggested both DRF model and TEF were consistent. In addition, the DRF values of PCB congeners obtained from this study were well correlated with AhR binding affinity based on in vitro test (r 2 = 0.63, p < 0.01) (Safe et al, 1985;Mekenyan et al, 1996), indicating that the model was well-directed to predict the toxicity of PCB congeners. However, the DRF values were not correlated to the lipophilicity of PCB molecules such as log K ow values (Svendsgaard et al, 1997).…”

Section: Wwwfrontiersinorgsupporting

confidence: 53%

“…Results of the Mulliken analysis were consistent with similarity factors 3 (both para positions chlorinated) and 4 (two or more meta positions chlorinated). Furthermore, + was found to be consistently larger than − across all sites Mekenyan et al (1996) and Safe et al (1985); The log K ow values of PCB congeners from Svendsgaard et al (1997). FIGURE 3 | Average site-specific reactivity of PCBs.…”

Section: First Principles Model Of Toxicitymentioning

confidence: 99%

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A comprehensive model for chemical bioavailability and toxicity of organic chemicals based on first principles

et al. 2014

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Here, we present a novel model to predict the toxicity and bioavailability of polychlorinated biphenyls (PCBs) as model compounds based on a first principles approach targeting basic electronic characteristics. The predictive model is based on an initio density functional theory. The model suggests HOMO-LUMO energy gap as the overarching indicator of PCBs toxicity, which was shown to be the primary factor predicting toxicity, but not the only factor. The model clearly explains why chlorination of both para positions is required for maximum toxic potency. To rank toxic potency, the "dipole moment" in relation to the most chemically active Cl-sites was critical. This finding was consistent with the accepted toxic equivalency factor (TEF) model for these molecules, and was also able to improve on ranking toxic potency of PCBs with similar TEFs. Predictions of HOMO-LUMO gap made with the model were consistent with measured values determined by synchrotron based X-ray spectroscopy for a subset of PCBs. HOMO-LUMO gap can also be used to predict bioaccumulation of PCBs. Overall, the new model provides an in silico method to screen a wide range of chemicals to predict their toxicity and bioavailability to act as an AhR agonist.

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Section: Wwwfrontiersinorgsupporting

confidence: 53%

Section: First Principles Model Of Toxicitymentioning

confidence: 99%

A comprehensive model for chemical bioavailability and toxicity of organic chemicals based on first principles

et al. 2014

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“…The aryl hydrocarbon receptor (AhR), an intracellular protein that mediates the induction of hepatic cytochrome P450IA1 and related enzymes, such as aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin-O-deethylase (EROD), is also an important target for the biological and toxicological responses evoked by PCBs. 4,5 Fusion enthalpy, an important physical property of the solid state, reflects the molecular packing in the crystalline states of PCBs. The coplanarity of the phenyl rings is strongly influenced by the degree of ortho-substitution, and this is an important feature that facilitates the binding of PCBs to biological receptors such as AhR.…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Quantitative Structure−Property Relationship (3D-QSPR) Models for Prediction of Thermodynamic Properties of Polychlorinated Biphenyls (PCBs): Enthalpy of Sublimation

Puri

Chickos

Welsh

2002

J. Chem. Inf. Comput. Sci.

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Comparative Molecular Field Analysis (CoMFA) has been used to develop three-dimensional quantitative structure-property relationship (3D-QSPR) models for the fusion enthalpy at the melting point (∆ fus H m (T fus )) of a representative set of polychlorinated biphenyls (PCBs). Various alignment schemes, such as inertial, as is, atom fit, and field fit, were used in this study to evaluate the predictive capabilities of the models. The CoMFA models have also been derived using partial atomic charges calculated from the electrostatic potential (ESP) and Gasteiger-Marsili (GM) methods. The combination of atom fit alignment and GM charges yielded the greatest self-consistency (r 2 ) 0.955) and internal predictive ability (r cv 2 ) 0.783). This CoMFA model was used to predict ∆ fus H m (T fus ) of the entire set of 209 PCB congeners, including 193 PCB congeners for which experimental values are unavailable. The CoMFA-predicted values, combined with previous estimations of vaporization and sublimation enthalpies, were used to construct a thermodynamic cycle that validated the internal self-consistency of the predictions for these three thermodynamic properties. The CoMFApredicted values of fusion enthalpy were also used to calculate aqueous solubilities of PCBs using Mobile Order and Disorder Theory. The agreement between calculated and experimental values of solubility at 298.15 K, characterized by a standard deviation of ( 0.41 log units, demonstrates the utility of CoMFApredicted values of fusion enthalpies to calculate aqueous solubilities of PCBs.

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“…Instead of focussing on minimum-energy conformations of the molecules, the dynamic QSAR approach was employed [25][26][27][28] in combination with a recently introduced genetic algorithm for generating sets of conformationally most different structures [29]. After generation and AM1 optimization of initial conformers for each molecule, the selection of active conformers is based on selected 3D-structure-specific electronic or geometric parameters (e.g.…”

Section: Dynamic Qsar Methods and Molecular Descriptorsmentioning

confidence: 99%

QSAR Modeling of Antimycobacterial Activity and Activity Against Other Bacteria of 3-Formyl Rifamycin SV Derivatives

Dimov

Nedyalkova

Haladjova

et al. 2001

Quant. Struct.-Act. Relat.

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Rifamycins form a class of antibiotics with a specific potency as drug against tuberculosis via inhibition of the DNA-dependent RNA polymerase. In the present study, literature data on the antibacterial potency against Mycobacterium tuberculosis and other bacteria of 53 derivatives of 3-formyl rifamycin SV are subjected to a QSAR analysis using AM1-based quantum chemical descriptors and the recently introduced dynamic approach that allows explicit consideration of the conformational space of properly generated 3D structures. Data pre-treatment includes normalization of the minimum inhibition concentration (MIC) values of ordinary bacteria using the well-known antituberculosis drug rifampicine as reference compound (RIA), and averaging over the different strains as motivated by a mathematical analysis of the two-step inhibition process. For both this generalized potency against ordinary bacteria and the antimycobacterial activity, QSAR modelling yields 3-variable regression equations with acceptable statistics for screening purposes (r 2 around 0.60), which however differ partly in the stepwise-selected molecular descriptors and the respective conformers. While both types of activity are increased by increasing HOMO energy reflecting an increased electron donor capability and tendency to undergo hydroquinone-semiquinone-quinone oxidation, the models differ in the best 2nd and 3rd local quantum chemical descriptors, pointing to partially conflicting electronic structure requirements for optimal antimycobacterial activity and generalized activity against other bacteria. The discussion includes a detailed mechanistic analysis of the underlying bioreactivity aspects.

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A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics.

Cited by 80 publications

References 30 publications

A comprehensive model for chemical bioavailability and toxicity of organic chemicals based on first principles

A comprehensive model for chemical bioavailability and toxicity of organic chemicals based on first principles

Three-Dimensional Quantitative Structure−Property Relationship (3D-QSPR) Models for Prediction of Thermodynamic Properties of Polychlorinated Biphenyls (PCBs): Enthalpy of Sublimation

QSAR Modeling of Antimycobacterial Activity and Activity Against Other Bacteria of 3-Formyl Rifamycin SV Derivatives

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