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

Authors
Gim, Hyo JinChoi, Yong-SungLi, HuaKim, Yoon-JungRyu, Jae-HaJeon, Raok
Issue Date
Oct-2018
Publisher
MDPI
Keywords
PPAR; agonist; indole; scaffold; tuning
Citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.19, no.10
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume
19
Number
10
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/4237
DOI
10.3390/ijms19103032
ISSN
1661-6596
Abstract
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- agonist than pioglitazone and our previous hit compound. Molecular docking studies may suggest the binding between compound 12 and PPAR-, rationalizing its high activity.
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