Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.

As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ,...

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Autores principales:	Li-Song Zhang, Shu-Qing Wang, Wei-Ren Xu, Run-Ling Wang, Jing-Fang Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9250f83d504e40b6929ec9013fde4d17
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spelling	oai:doaj.org-article:9250f83d504e40b6929ec9013fde4d172021-11-18T08:10:22ZScaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.1932-620310.1371/journal.pone.0048453https://doaj.org/article/9250f83d504e40b6929ec9013fde4d172012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23119024/?tool=EBIhttps://doaj.org/toc/1932-6203As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.Li-Song ZhangShu-Qing WangWei-Ren XuRun-Ling WangJing-Fang WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e48453 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Li-Song Zhang Shu-Qing Wang Wei-Ren Xu Run-Ling Wang Jing-Fang Wang Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
description	As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.
format	article
author	Li-Song Zhang Shu-Qing Wang Wei-Ren Xu Run-Ling Wang Jing-Fang Wang
author_facet	Li-Song Zhang Shu-Qing Wang Wei-Ren Xu Run-Ling Wang Jing-Fang Wang
author_sort	Li-Song Zhang
title	Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
title_short	Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
title_full	Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
title_fullStr	Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
title_full_unstemmed	Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
title_sort	scaffold-based pan-agonist design for the pparα, pparβ and pparγ receptors.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/9250f83d504e40b6929ec9013fde4d17
work_keys_str_mv	AT lisongzhang scaffoldbasedpanagonistdesignforthepparapparbandppargreceptors AT shuqingwang scaffoldbasedpanagonistdesignforthepparapparbandppargreceptors AT weirenxu scaffoldbasedpanagonistdesignforthepparapparbandppargreceptors AT runlingwang scaffoldbasedpanagonistdesignforthepparapparbandppargreceptors AT jingfangwang scaffoldbasedpanagonistdesignforthepparapparbandppargreceptors
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Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.

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