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Structure–Function Relationships and Therapeutic Potential of Non-Covalent PPARγ Inverse Agonists

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARγ) is a validated therapeutic target for type 2 diabetes (T2D), but current FDA-approved agonists such as the glitazones are limited by adverse effects. SR10171, a non-covalent partial inverse agonist with modest binding potency, improves insulin sensitivity in mice without bone loss or marrow adiposity. Here, we characterize a series of SR10171 analogs to define structure-function relationships using biochemical assays, hydrogen-deuterium exchange (HDX), and computational modeling. Analogs featuring flipped indole scaffolds with alkyl substitutions exhibited 10-100-fold enhanced binding to PPARγ while retaining inverse agonist activity. HDX and molecular dynamic simulations revealed that ligand-induced dynamics within ligand-binding pocket and AF2 domain correlate with enhanced receptor binding. Lead analogs restored receptor activity in loss-of-function PPAR variants and improved insulin sensitivity in adipocytes from a diabetic patient. These findings provide mechanistic insights into non-covalent PPARγ modulation establishing a framework for developing safer, next-generation insulin sensitizers for metabolic disease therapy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kuang-Ting Kuo

LAB HEAD: Patrick R.

PROVIDER: PXD066095 | Pride | 2025-11-15

REPOSITORIES: Pride

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			Action	DRS
	20240106_DMSO_SR34048_SR35795_SR10171_DMSO_10s_REP1.raw	Raw
	20240106_DMSO_SR34048_SR35795_SR10171_DMSO_10s_REP2.raw	Raw
	20240106_DMSO_SR34048_SR35795_SR10171_DMSO_10s_REP3.raw	Raw
	20240106_DMSO_SR34048_SR35795_SR10171_DMSO_14400s_REP1.raw	Raw
	20240106_DMSO_SR34048_SR35795_SR10171_DMSO_14400s_REP2.raw	Raw

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