Identification of a novel selective PPAR$γ$ ligand with a unique binding mode and improved therapeutic profile in vitro

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

doi:10.1038/srep41487

Identification of a novel selective PPAR$$γ$$ ligand with a unique binding mode and improved therapeutic profile in vitro

Journal Article · Fri Jan 27 00:00:00 EST 2017 · Scientific Reports

DOI:https://doi.org/10.1038/srep41487· OSTI ID:1438869

Yi, Wei ^[1]; Shi, Jingjing ^[2]; Zhao, Guanguan ^[2]; Zhou, X. Edward ^[3]; Suino-Powell, Kelly ^[3]; Melcher, Karsten ^[3]; Xu, H. Eric ^[4]

Guangzhou Medical Univ. (China); Chinese Academy of Sciences (CAS), Shanghai (China)
Chinese Academy of Sciences (CAS), Shanghai (China)
Van Andel Research Inst., Grand Rapids, MI
Chinese Academy of Sciences (CAS), Shanghai (China); Van Andel Research Inst., Grand Rapids, MI

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Amway; Institutes for Drug Discovery and Development; Jay and Betty Van Andel Foundation; National Natural Science Foundation of China (NSFC); Youth Innovation Promotion Association Chinese Academy of Sciences (CAS), the Shanghai Municipal Natural Science Foundation

OSTI ID:: 1438869

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 7; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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