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Identification of a Novel Selective PPARγ Ligand With a Unique Binding Mode and Improved Therapeutic Profile in Vitro

Identification of a Novel Selective PPARγ Ligand With a Unique Binding Mode and Improved Therapeutic Profile in Vitro

Wei Yi, Jingjing Shi, Guanguan Zhao, X Edward Zhou, Kelly Suino-Powell, Karsten Melcher, H Eric Xu

Sci Rep. 2017 Jan 27;7:41487.

PMID: 28128331

Abstract:

Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPARγ-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARγ with improved insulin sensitivity due to its ability to bind PPARγ with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARγ ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPARγ with advantages over current TZD drugs.

Chemicals Related in the Paper:

Catalog Number	Product Name	CAS Number	Price
AP1026353207	Telmisartan Related Compound B	1026353-20-7	Price
AP1282554351	Telmisartan Related Compound A	1282554-35-1	Price
IAR4246435	PPARγ Modulator, SR1664		Price

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