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Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have developed a virtual screening procedure to identify potential ligands to the aryl hydrocarbon receptor (AhR) among a set of industrial chemicals. AhR is a key target for dioxin-like compounds, which is related to these compounds’ potential to induce cancer and a wide range of endocrine and immune system related effects. The virtual screening procedure included an initial filtration aiming at identifying chemicals with structural similarities to 66 known AhR binders, followed by three enrichment methods run in parallel. These include two ligand-based methods (structural fingerprints and nearest neighbor analysis) and one structure-based method using an AhR homology model. A set of 6,445 commonly used industrial chemicals was processed, and each step identified unique potential ligands. Seven compounds were identified by all three enrichment methods, and these compounds included known activators and suppressors of AhR. Only approximately 0.7% (41 compounds) of the studied industrial compounds was identified as potential AhR ligands and among these, 28 compounds have to our knowledge not been tested for AhR-mediated effects or have been screened with low purity. We suggest assessment of AhR-related activities of these compounds and in particular 2-chlorotrityl chloride, 3-p-hydroxyanilino-carbazole, and 3-(2-chloro-4-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one.

National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-139486OAI: oai:DiVA.org:umu-139486DiVA: diva2:1141203
Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2017-09-14
In thesis
1. Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
Open this publication in new window or tab >>Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are omnipresent and persistent environmental pollutants. In particular, 29 congeners are of special concern, and these are usually referred to as dioxin-like compounds (DLCs). In the European Union, the risks associated with DLCs in food products are estimated by a weighted sum of the DLCs’ concentrations. These weights, also called toxic equivalency factors (TEFs), compare the DLCs’ potencies to the most toxic congener, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2378- TCDD). The toxicological effects of PCDD/Fs and PCBs are diverse, ranging from chloracne and immunological effects in humans to severe weight loss, thymic atrophy, hepatotoxicity, immunotoxicity, endocrine disruption, and carcinogenesis in rodents.

Here, the molecular structures of DLCs were used as the basis to study the congeneric differences in in vitro data from both human and rodent cell responses related to the aryl hydrocarbon receptor (AhR). Based on molecular orbital densities and partial charges, we developed new ways to describe DLCs, which proved to be useful in quantitative structure-activity relationship modeling. This thesis also provides a new approach, the calculation of the consensus toxicity factor (CTF), to condense information from a battery of screening tests. The current TEFs used to estimate the risk of DLCs in food are primarily based on in vivo information from rat and mouse experiments. Our CTFs, based on human cell responses, show clear differences compared to the current TEFs. For instance, the CTF of 23478-PeCDF is as high as the CTF for 2378-TCDD, and the CTF of PCB 126 is 30 times lower than the corresponding TEF. Both of these DLCs are common congeners in fish in the Baltic Sea. Due to the severe effects of DLCs and their impact on environmental and human health, it is crucial to determine if other compounds have similar effects. To find such compounds, we developed a virtual screening protocol and applied it to a set of 6,445 industrial chemicals. This protocol included a presumed 3D representation of AhR and the structural and chemical properties of known AhR ligands. This screening resulted in a priority list of 28 chemicals that we identified as potential AhR ligands.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 66 p.
Keyword
dioxin-like compounds, multivariate analysis, toxic equivalency factor, quantitative structure-activity relationship, descriptors, virtual screening, in vitro, species variation, aryl hydrocarbon receptor
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-139487 (URN)978-91-7601-736-4 (ISBN)
Public defence
2017-10-19, KB.E3.01 (Lilla Hörsalen), KBC-huset, Umeå, 13:00 (English)
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Supervisors
Available from: 2017-09-28 Created: 2017-09-14 Last updated: 2017-10-02Bibliographically approved

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