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Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery
- Source :
- Chemical Science. 11:2260-2268
- Publication Year :
- 2020
- Publisher :
- Royal Society of Chemistry (RSC), 2020.
-
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.
- Subjects :
- 0303 health sciences
Chemistry
Drug discovery
Allosteric regulation
Regulator
Lipid metabolism
General Chemistry
Pharmacology
Partial agonist
03 medical and health sciences
0302 clinical medicine
Therapeutic index
In vivo
030220 oncology & carcinogenesis
Glucose homeostasis
030304 developmental biology
Subjects
Details
- ISSN :
- 20416539 and 20416520
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Chemical Science
- Accession number :
- edsair.doi...........5ff3e33f9129c2334c7b12d769e245f1