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Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, appl...

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Detalles Bibliográficos
Autores principales: Guasch, Laura, Sala, Esther, Castell-Auví, Anna, Cedó, Lidia, Liedl, Klaus R., Wolber, Gerhard, Muehlbacher, Markus, Mulero, Miquel, Pinent, Montserrat, Ardévol, Anna, Valls, Cristina, Pujadas, Gerard, Garcia-Vallvé, Santiago
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511273/
https://www.ncbi.nlm.nih.gov/pubmed/23226391
http://dx.doi.org/10.1371/journal.pone.0050816
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author Guasch, Laura
Sala, Esther
Castell-Auví, Anna
Cedó, Lidia
Liedl, Klaus R.
Wolber, Gerhard
Muehlbacher, Markus
Mulero, Miquel
Pinent, Montserrat
Ardévol, Anna
Valls, Cristina
Pujadas, Gerard
Garcia-Vallvé, Santiago
author_facet Guasch, Laura
Sala, Esther
Castell-Auví, Anna
Cedó, Lidia
Liedl, Klaus R.
Wolber, Gerhard
Muehlbacher, Markus
Mulero, Miquel
Pinent, Montserrat
Ardévol, Anna
Valls, Cristina
Pujadas, Gerard
Garcia-Vallvé, Santiago
author_sort Guasch, Laura
collection PubMed
description BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists.
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spelling pubmed-35112732012-12-05 Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation Guasch, Laura Sala, Esther Castell-Auví, Anna Cedó, Lidia Liedl, Klaus R. Wolber, Gerhard Muehlbacher, Markus Mulero, Miquel Pinent, Montserrat Ardévol, Anna Valls, Cristina Pujadas, Gerard Garcia-Vallvé, Santiago PLoS One Research Article BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists. Public Library of Science 2012-11-30 /pmc/articles/PMC3511273/ /pubmed/23226391 http://dx.doi.org/10.1371/journal.pone.0050816 Text en © 2012 Guasch et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Guasch, Laura
Sala, Esther
Castell-Auví, Anna
Cedó, Lidia
Liedl, Klaus R.
Wolber, Gerhard
Muehlbacher, Markus
Mulero, Miquel
Pinent, Montserrat
Ardévol, Anna
Valls, Cristina
Pujadas, Gerard
Garcia-Vallvé, Santiago
Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
title Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
title_full Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
title_fullStr Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
title_full_unstemmed Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
title_short Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
title_sort identification of ppargamma partial agonists of natural origin (i): development of a virtual screening procedure and in vitro validation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511273/
https://www.ncbi.nlm.nih.gov/pubmed/23226391
http://dx.doi.org/10.1371/journal.pone.0050816
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