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Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

The comprehensive understanding of the precise mode of action and/or adverse outcome pathway (MoA/AOP) of chemicals has become a key step toward the development of a new generation of predictive toxicology tools. One of the challenges of this process is to test the feasibility of the molecular model...

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Autores principales: Tsakovska, Ivanka, Al Sharif, Merilin, Alov, Petko, Diukendjieva, Antonia, Fioravanzo, Elena, Cronin, Mark T. D., Pajeva, Ilza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057697/
https://www.ncbi.nlm.nih.gov/pubmed/24857909
http://dx.doi.org/10.3390/ijms15057651
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author Tsakovska, Ivanka
Al Sharif, Merilin
Alov, Petko
Diukendjieva, Antonia
Fioravanzo, Elena
Cronin, Mark T. D.
Pajeva, Ilza
author_facet Tsakovska, Ivanka
Al Sharif, Merilin
Alov, Petko
Diukendjieva, Antonia
Fioravanzo, Elena
Cronin, Mark T. D.
Pajeva, Ilza
author_sort Tsakovska, Ivanka
collection PubMed
description The comprehensive understanding of the precise mode of action and/or adverse outcome pathway (MoA/AOP) of chemicals has become a key step toward the development of a new generation of predictive toxicology tools. One of the challenges of this process is to test the feasibility of the molecular modelling approaches to explore key molecular initiating events (MIE) within the integrated strategy of MoA/AOP characterisation. The description of MoAs leading to toxicity and liver damage has been the focus of much interest. Growing evidence underlines liver PPARγ ligand-dependent activation as a key MIE in the elicitation of liver steatosis. Synthetic PPARγ full agonists are of special concern, since they may trigger a number of adverse effects not observed with partial agonists. In this study, molecular modelling was performed based on the PPARγ complexes with full agonists extracted from the Protein Data Bank. The receptor binding pocket was analysed, and the specific ligand-receptor interactions were identified for the most active ligands. A pharmacophore model was derived, and the most important pharmacophore features were outlined and characterised in relation to their specific role for PPARγ activation. The results are useful for the characterisation of the chemical space of PPARγ full agonists and could facilitate the development of preliminary filtering rules for the effective virtual ligand screening of compounds with PPARγ full agonistic activity.
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spelling pubmed-40576972014-06-16 Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis Tsakovska, Ivanka Al Sharif, Merilin Alov, Petko Diukendjieva, Antonia Fioravanzo, Elena Cronin, Mark T. D. Pajeva, Ilza Int J Mol Sci Article The comprehensive understanding of the precise mode of action and/or adverse outcome pathway (MoA/AOP) of chemicals has become a key step toward the development of a new generation of predictive toxicology tools. One of the challenges of this process is to test the feasibility of the molecular modelling approaches to explore key molecular initiating events (MIE) within the integrated strategy of MoA/AOP characterisation. The description of MoAs leading to toxicity and liver damage has been the focus of much interest. Growing evidence underlines liver PPARγ ligand-dependent activation as a key MIE in the elicitation of liver steatosis. Synthetic PPARγ full agonists are of special concern, since they may trigger a number of adverse effects not observed with partial agonists. In this study, molecular modelling was performed based on the PPARγ complexes with full agonists extracted from the Protein Data Bank. The receptor binding pocket was analysed, and the specific ligand-receptor interactions were identified for the most active ligands. A pharmacophore model was derived, and the most important pharmacophore features were outlined and characterised in relation to their specific role for PPARγ activation. The results are useful for the characterisation of the chemical space of PPARγ full agonists and could facilitate the development of preliminary filtering rules for the effective virtual ligand screening of compounds with PPARγ full agonistic activity. Molecular Diversity Preservation International (MDPI) 2014-05-05 /pmc/articles/PMC4057697/ /pubmed/24857909 http://dx.doi.org/10.3390/ijms15057651 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Tsakovska, Ivanka
Al Sharif, Merilin
Alov, Petko
Diukendjieva, Antonia
Fioravanzo, Elena
Cronin, Mark T. D.
Pajeva, Ilza
Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
title Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
title_full Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
title_fullStr Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
title_full_unstemmed Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
title_short Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
title_sort molecular modelling study of the pparγ receptor in relation to the mode of action/adverse outcome pathway framework for liver steatosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057697/
https://www.ncbi.nlm.nih.gov/pubmed/24857909
http://dx.doi.org/10.3390/ijms15057651
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