Identification and Structural Insight of an Effective PPARγ Modulator with Improved Therapeutic Index for Anti-diabetic Drug Discovery

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2020 Mar 20

PMID 32190280

Citations 6

Authors

Haowen Jiang

X Edward Zhou

Jingjing Shi

Zhi Zhou

Guanguan Zhao

Xinwen Zhang

Yili Sun

Kelly Suino-Powell

Lei Ma

Hui Gao

Xiyong Yu

Jia Li

Jingya Li

Karsten Melcher

H Eric Xu

Wei Yi

Affiliations

Soon will be listed here.

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 and 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.

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