Editor’s Highlight: Microbial-Derived 1,4-Dihydroxy-2-naphthoic Acid and Related Compounds as Aryl Hydrocarbon Receptor Agonists/Antagonists: Structure–Activity Relationships and Receptor Modeling
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1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derived metabolite that binds the aryl hydrocarbon receptor (AhR) and exhibits anti-inflammatory activity in the gut. The structure-dependent AhR activity of hydroxyl/carboxy-substituted naphthoic acids (NAs) was determined in young adult mouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1 mRNAs as Ah-responsive genes. Compounds used in this study include 1,4-, 3,5-, and 3,7-DHNA, 1,4-dimethoxy-2-naphthoic acid (1,4-DMNA), 1- and 4-hydroxy-2-naphthoic acid (1-HNA, 4-HNA), 1- and 2-naphthoic acid (1-NA, 2-NA), and 1- and 2-naphthol (1-NOH, 2-NOH). 1,4-DHNA was the most potent compound among hydroxyl/carboxy naphthalene derivatives, and the fold induction response for CYP1A1 and CYP1B1 was similar to that observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in YAMC and Caco2 cells. 1- and 4-HNA were less potent than 1,4-DHNA but induced maximal (TCDD-like) response for CYP1B1 (both cell lines) and CYP1A1 (Caco2 cells). With the exception of 1- and 2-NA, all compounds significantly induced Cyp1b1 in YAMC cells and these responses were not observed in AhR-deficient YAMC cells generated using CRISPR/Cas9 technology. In addition, we also observed that 1- and 2-NOH (and 1,4-DHNA) were weak AhR agonists, and 1- and 2-NOH also exhibited partial AhR antagonist activity. Structure-activity relationship studies for CYP1A1 but not CYP1B1 were similar in both cell lines, and CYP1A1 induction required one or both 1,4-dihydroxy substituents and activity was significantly enhanced by the 2-carboxyl group. We also used computational analysis to show that 1,4-DHNA and TCDD share similar interactions within the AhR binding pocket and differ primarily due to the negatively charged group of 1,4-DHNA.
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Recent docking studies allowed prediction of the binding modes of several AhR ligands and led to the discovery of novel AhR agonists and SAhRMs.
“On the basis of these novel approaches, recent docking studies not only allowed prediction of the binding modes of several AhR ligands but also led to the discovery of novel AhR agonists and SAhRMs25,27–30.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [28]
The Computational homology modeling and Modeling of TCDD and 1,4-DHNA Interactions sections (pages unavailable) report docking-based predictions of binding modes for two AhR ligands. The Discussion describes newly identified partial AhR antagonists, but attributes that finding to cell and binding assays, not docking; our copy does not identify them as SAhRMs. Thus this source supports the binding-mode portion, not the claimed docking-led discovery. (LLM, conf=0.86)
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Modeling the binding of diverse ligands within the Ah receptor ligand binding domain
Giani Tagliabue, S., Faber, S. C., Motta, S., Denison, M. S., & Bonati, L. (2019) · Scientific Reports · doi:10.1038/s41598-019-47138-z · Cited by 106 · see citing works
Self-citation
- Authors
- Cheng, Y., Jin, U.-H., Davidson, L. A., Chapkin, R. S., Jayaraman, A., Tamamis, P., Orr, A., Allred, C., Denison, M. S., Soshilov, A., Weaver, E., & Safe, S.
- Affiliations
- Texas A&M University (US)
- University of California, Davis (US)
- Corresponding author
- Safe, Stephen
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-11-11
- Volume
- 155
- Issue
- 2
- Pages
- 458-473
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC5291215
- OpenAlex
- W2555394033
- Cited by
- 48
- References
- 61
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 9 · 2022: 8 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 3
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Cancer Institute (R35CA197707, R01CA202697)
- National Institute of Environmental Health Sciences (P30ES023512, R01ES007685, R01ES025713)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- 1,4-dihydroxy-2-naphthoic acid, aryl hydrocarbon receptor, bacterial metabolites, naphthoic acid, structure-activity relationship, CYP1A1, CYP1B1, AhR antagonists, anti-inflammatory activity, colonic epithelial cells, Caco-2 cells, CRISPR/Cas9 knockout, 2,3,7,8-tetrachlorodibenzo-p-dioxin, naphthol derivatives, gut microbiota metabolites
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Cell Line, Guinea Pigs, Humans, Models, Theoretical, Naphthalenes, Naphthols, Structure-Activity Relationship, Receptors, Aryl Hydrocarbon, Caco-2 Cells, Cytochrome P-450 CYP1A1, Mice, Cytochrome P-450 CYP1B1
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