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Molecular Docking of Natural Compounds for Potential Inhibition of AhR

The aryl hydrocarbon receptor (AhR) is a highly conserved environmental sensor, historically known for mediating the toxicity of xenobiotics. It is involved in numerous cellular processes such as differentiation, proliferation, immunity, inflammation, homeostasis, and metabolism. It exerts a central...

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Autores principales: Giordano, Deborah, Facchiano, Angelo, Moccia, Stefania, Meola, Anna Maria Iole, Russo, Gian Luigi, Spagnuolo, Carmela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217167/
https://www.ncbi.nlm.nih.gov/pubmed/37238771
http://dx.doi.org/10.3390/foods12101953
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author Giordano, Deborah
Facchiano, Angelo
Moccia, Stefania
Meola, Anna Maria Iole
Russo, Gian Luigi
Spagnuolo, Carmela
author_facet Giordano, Deborah
Facchiano, Angelo
Moccia, Stefania
Meola, Anna Maria Iole
Russo, Gian Luigi
Spagnuolo, Carmela
author_sort Giordano, Deborah
collection PubMed
description The aryl hydrocarbon receptor (AhR) is a highly conserved environmental sensor, historically known for mediating the toxicity of xenobiotics. It is involved in numerous cellular processes such as differentiation, proliferation, immunity, inflammation, homeostasis, and metabolism. It exerts a central role in several conditions such as cancer, inflammation, and aging, acting as a transcription factor belonging to the basic helix–loop–helix/Per-ARNT-Sim (bHLH-PAS) protein family. A key step in the canonical AhR activation is AhR-ARNT heterodimerization followed by the binding to the xenobiotic-responsive elements (XREs). The present work aims to investigate the potential AhR inhibitory activity of selected natural compounds. Due to the absence of a complete structure of human AhRs, a model consisting of the bHLH, the PAS A, and the PAS B domains was constructed. Blind and focused docking simulations revealed the presence of further binding pockets, different from the canonical one presented in the PAS B domain, which could be important for AhR inhibition due to the possibility to impede AhR:ARNT heterodimerization, either preventing conformational changes or masking crucial sites necessary for protein–protein interaction. Two of the compounds retrieved from the docking simulations, i.e., β-carotene and ellagic acid, confirmed their capacity of inhibiting benzo[a]pyrene (BaP)-induced AhR activation in in vitro tests on the human hepatoma cell line HepG2, validating the efficacy of the computational approach.
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spelling pubmed-102171672023-05-27 Molecular Docking of Natural Compounds for Potential Inhibition of AhR Giordano, Deborah Facchiano, Angelo Moccia, Stefania Meola, Anna Maria Iole Russo, Gian Luigi Spagnuolo, Carmela Foods Article The aryl hydrocarbon receptor (AhR) is a highly conserved environmental sensor, historically known for mediating the toxicity of xenobiotics. It is involved in numerous cellular processes such as differentiation, proliferation, immunity, inflammation, homeostasis, and metabolism. It exerts a central role in several conditions such as cancer, inflammation, and aging, acting as a transcription factor belonging to the basic helix–loop–helix/Per-ARNT-Sim (bHLH-PAS) protein family. A key step in the canonical AhR activation is AhR-ARNT heterodimerization followed by the binding to the xenobiotic-responsive elements (XREs). The present work aims to investigate the potential AhR inhibitory activity of selected natural compounds. Due to the absence of a complete structure of human AhRs, a model consisting of the bHLH, the PAS A, and the PAS B domains was constructed. Blind and focused docking simulations revealed the presence of further binding pockets, different from the canonical one presented in the PAS B domain, which could be important for AhR inhibition due to the possibility to impede AhR:ARNT heterodimerization, either preventing conformational changes or masking crucial sites necessary for protein–protein interaction. Two of the compounds retrieved from the docking simulations, i.e., β-carotene and ellagic acid, confirmed their capacity of inhibiting benzo[a]pyrene (BaP)-induced AhR activation in in vitro tests on the human hepatoma cell line HepG2, validating the efficacy of the computational approach. MDPI 2023-05-11 /pmc/articles/PMC10217167/ /pubmed/37238771 http://dx.doi.org/10.3390/foods12101953 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Giordano, Deborah
Facchiano, Angelo
Moccia, Stefania
Meola, Anna Maria Iole
Russo, Gian Luigi
Spagnuolo, Carmela
Molecular Docking of Natural Compounds for Potential Inhibition of AhR
title Molecular Docking of Natural Compounds for Potential Inhibition of AhR
title_full Molecular Docking of Natural Compounds for Potential Inhibition of AhR
title_fullStr Molecular Docking of Natural Compounds for Potential Inhibition of AhR
title_full_unstemmed Molecular Docking of Natural Compounds for Potential Inhibition of AhR
title_short Molecular Docking of Natural Compounds for Potential Inhibition of AhR
title_sort molecular docking of natural compounds for potential inhibition of ahr
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217167/
https://www.ncbi.nlm.nih.gov/pubmed/37238771
http://dx.doi.org/10.3390/foods12101953
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