2. Academic Validation
  3. Structure-based discovery of a novel nuclear receptor PPARγ inhibitor: Implications for obesity and metabolic disease intervention

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

  • Biomed Pharmacother. 2025 Oct 7:192:118615. doi: 10.1016/j.biopha.2025.118615.
Phum Tachachartvanich 1,  Rapeepat Sangsuwan 2,  Nonticha Ngernpisutsilp 3,  Hunsa Prawat 4,  Wirongrong Kaweetripob 5,  Mathuros Ruchirawat 6,  Somsak Ruchirawat 7
Affiliations

Affiliations

  • 1 Laboratory 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.
  • 2 Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand; Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok 10210, Thailand. Electronic address: rapeepat@cri.or.th.
  • 3 Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand.
  • 4 Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand; Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok 10210, Thailand.
  • 5 Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok 10210, Thailand.
  • 6 Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand.
  • 7 Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand; Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand; Chemical Sciences Program, Chulabhorn Graduate Institute, Bangkok 10210, Thailand.
PMID: 41061585 DOI: 10.1016/j.biopha.2025.118615
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.

Keywords

Adipogenesis; Drug discovery; Metabolic disease; Nuclear receptor; Obesity; PPARγ.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16578
    99.79%, PPARγ拮抗剂
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