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Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach

Peroxisome proliferator-activated receptors (PPARs) are important targets in metabolic diseases including obesity, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease. Recently, they have been highlighted as attractive targets for the treatment of cardiovascular diseases and chronic...

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Autores principales: Gim, Hyo Jin, Choi, Yong-Sung, Li, Hua, Kim, Yoon-Jung, Ryu, Jae-Ha, Jeon, Raok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213020/
https://www.ncbi.nlm.nih.gov/pubmed/30287791
http://dx.doi.org/10.3390/ijms19103032
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author Gim, Hyo Jin
Choi, Yong-Sung
Li, Hua
Kim, Yoon-Jung
Ryu, Jae-Ha
Jeon, Raok
author_facet Gim, Hyo Jin
Choi, Yong-Sung
Li, Hua
Kim, Yoon-Jung
Ryu, Jae-Ha
Jeon, Raok
author_sort Gim, Hyo Jin
collection PubMed
description Peroxisome proliferator-activated receptors (PPARs) are important targets in metabolic diseases including obesity, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease. Recently, they have been highlighted as attractive targets for the treatment of cardiovascular diseases and chronic myeloid leukemia. The PPAR agonist structure is consists of a polar head, a hydrophobic tail, and a linker. Each part interacts with PPARs through hydrogen bonds or hydrophobic interactions to stabilize target protein conformation, thus increasing its activity. Acidic head is essential for PPAR agonist activity. The aromatic linker plays an important role in making hydrophobic interactions with PPAR as well as adjusting the head-to-tail distance and conformation of the whole molecule. By tuning the scaffold of compound, the whole molecule could fit into the ligand-binding domain to achieve proper binding mode. We modified indol-3-ylacetic acid scaffold to (indol-1-ylmethyl)benzoic acid, whereas 2,4-dichloroanilide was fixed as the hydrophobic tail. We designed, synthesized, and assayed the in vitro activity of novel indole compounds with (indol-1-ylmethyl)benzoic acid scaffold. Compound 12 was a more potent PPAR-γ agonist than pioglitazone and our previous hit compound. Molecular docking studies may suggest the binding between compound 12 and PPAR-γ, rationalizing its high activity.
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spelling pubmed-62130202018-11-14 Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach Gim, Hyo Jin Choi, Yong-Sung Li, Hua Kim, Yoon-Jung Ryu, Jae-Ha Jeon, Raok Int J Mol Sci Article Peroxisome proliferator-activated receptors (PPARs) are important targets in metabolic diseases including obesity, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease. Recently, they have been highlighted as attractive targets for the treatment of cardiovascular diseases and chronic myeloid leukemia. The PPAR agonist structure is consists of a polar head, a hydrophobic tail, and a linker. Each part interacts with PPARs through hydrogen bonds or hydrophobic interactions to stabilize target protein conformation, thus increasing its activity. Acidic head is essential for PPAR agonist activity. The aromatic linker plays an important role in making hydrophobic interactions with PPAR as well as adjusting the head-to-tail distance and conformation of the whole molecule. By tuning the scaffold of compound, the whole molecule could fit into the ligand-binding domain to achieve proper binding mode. We modified indol-3-ylacetic acid scaffold to (indol-1-ylmethyl)benzoic acid, whereas 2,4-dichloroanilide was fixed as the hydrophobic tail. We designed, synthesized, and assayed the in vitro activity of novel indole compounds with (indol-1-ylmethyl)benzoic acid scaffold. Compound 12 was a more potent PPAR-γ agonist than pioglitazone and our previous hit compound. Molecular docking studies may suggest the binding between compound 12 and PPAR-γ, rationalizing its high activity. MDPI 2018-10-04 /pmc/articles/PMC6213020/ /pubmed/30287791 http://dx.doi.org/10.3390/ijms19103032 Text en © 2018 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gim, Hyo Jin
Choi, Yong-Sung
Li, Hua
Kim, Yoon-Jung
Ryu, Jae-Ha
Jeon, Raok
Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
title Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
title_full Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
title_fullStr Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
title_full_unstemmed Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
title_short Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
title_sort identification of a novel ppar-γ agonist through a scaffold tuning approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213020/
https://www.ncbi.nlm.nih.gov/pubmed/30287791
http://dx.doi.org/10.3390/ijms19103032
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