Download MendeleyIdentification and structural insight of an effective PPAR gamma modulator with improved therapeutic index for anti-diabetic drug discovery.
Jiang, H., Zhou, X.E., Shi, J., Zhou, Z., Zhao, G., Zhang, X., Sun, Y., Suino-Powell, K., Ma, L., Gao, H., Yu, X., Li, J., Li, J., Melcher, K., Xu, H.E., Yi, W.(2020) Chem Sci 11: 2260-2268
- PubMed: 32190280
- DOI: https://doi.org/10.1039/c9sc05487a
- Primary Citation of Related Structures:
6MS7 - PubMed Abstract:
Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARγ-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARγ modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs.
Organizational Affiliation:
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology , State Key Laboratory of Respiratory Disease , School of Pharmaceutical Sciences & the Fifth Affiliated Hospital , Guangzhou Medical University , Guangzhou , Guangdong 511436 , China . Email: yiwei@gzhmu.edu.cn.
