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Published on: November 15, 2013
Structure-based discovery of a novel nuclear receptor PPARγ inhibitor: Implications for obesity and metabolic disease
Phum Tachachartvanich1, Rapeepat Sangsuwan2, Nonticha Ngernpisutsilp3
1Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand.
Abstract:
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.
Insights
A novel compound, compound 3, effectively inhibits peroxisome proliferator-activated receptor gamma (PPARγ), offering a promising new strategy for combating obesity and improving metabolic health by suppressing fat cell development.
Area of Science:
- Molecular Biology
- Metabolic Disorders
- Drug Discovery
Background:
- Obesity is a global health crisis driven by complex metabolic dysregulation.
- Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of fat cell differentiation and metabolism, making it a significant therapeutic target.
- Inhibiting PPARγ activity presents an underexplored strategy for managing obesity and related metabolic conditions.
Purpose of the Study:
- To identify novel inhibitors of PPARγ using structure-based virtual screening.
- To evaluate the anti-adipogenic potential of identified compounds in vitro.
- To elucidate the mechanism of action of the most potent inhibitor.
Main Methods:
- Structure-based virtual screening of a diverse compound library (>1000 compounds) to identify potential PPARγ inhibitors.
- In vitro experimental validation of top candidates for PPARγ target engagement and anti-adipogenic activity in mouse and human adipocytes.
- Mechanism of action studies including PPARγ transactivation assays, transcriptome analysis, and molecular dynamics simulations.
Main Results:
- Compound 3 demonstrated superior anti-adipogenic activity compared to the known PPARγ inhibitor GW9662.
- Compound 3 dose-dependently inhibited PPARγ transactivation and downregulated key genes in the PPAR signaling pathway, adipocyte differentiation, and lipogenesis.
- Molecular dynamics simulations confirmed stable interactions of compound 3 within the PPARγ ligand-binding domain, supporting its inhibitory function.
Conclusions:
- Compound 3 is identified as a potent PPARγ inhibitor with significant anti-adipogenic effects.
- These findings highlight the therapeutic potential of PPARγ inhibition for obesity and associated metabolic disorders.
- The study validates nuclear receptor inhibition as a targeted therapeutic strategy.
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