Structure-based discovery of a novel nuclear receptor PPARγ inhibitor: Implications for obesity and metabolic disease intervention

Obesity is a chronic metabolic disorder adversely affecting billions of lives and posing a major public health challenge. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipogenesis and lipid metabolism, has emerged as a promising therapeutic target in obesity and associated metabolic diseases. Pharmacological inhibition of PPARγ represents a promising and underexplored strategy for suppressing adipocyte differentiation and improving metabolic health outcomes. Herein, a structure-based virtual screening was employed to identify potential PPARγ inhibitors from a curated library comprising over 1000 structurally diverse natural products and synthetic compounds. The top ten candidates predicted in silico were experimentally evaluated in vitro for PPARγ target engagement and anti-adipogenic activity in both mouse and human adipocytes. Among these, compound 3 consistently exhibited the most potent anti-adipogenic activity, surpassing GW9662, a well-characterized PPARγ inhibitor. Mechanistically, compound 3 inhibited PPARγ transactivation in a dose-dependent manner, assessed by PPARγ-mediated luciferase assay. Transcriptome of human adipocytes treated with compound 3 revealed a significant downregulation of genes involved in the PPAR signaling pathway, adipocyte differentiation, and lipogenesis, consistent with the validated gene expression profile. Additionally, molecular dynamics simulation indicated that compound 3 formed stable multivalent interactions with key amino acid residues within the PPARγ ligand-binding domain, hindering the receptor's activator-bound conformation and supporting its inhibitory effect. Collectively, these findings identify compound 3 as a potent PPARγ inhibitor with robust anti-adipogenic activity and therapeutic promise, which underscores the potential of nuclear receptor inhibition as a targeted strategy for treating obesity and related metabolic disorders.