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Open AccessArticle

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

Drug Information Research Institute, Research Institute of Pharmaceutical Sciences, SookmyungWomen’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Korea
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(10), 3032;
Received: 31 August 2018 / Revised: 27 September 2018 / Accepted: 2 October 2018 / Published: 4 October 2018
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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. View Full-Text
Keywords: PPAR; agonist; indole; scaffold; tuning PPAR; agonist; indole; scaffold; tuning
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MDPI and ACS Style

Gim, H.J.; Choi, Y.-S.; Li, H.; Kim, Y.-J.; Ryu, J.-H.; Jeon, R. Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach. Int. J. Mol. Sci. 2018, 19, 3032.

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