ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 13 - 2025 | doi: 10.3389/fchem.2025.1579445
This article is part of the Research TopicMedicinal and edible TCMs: Extraction and Isolation, Structural Elucidation, Pharmacological Evaluation, Structural Modification, and Quality ControlView all articles
Discovery of a novel binding pocket in PPAR for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis
Provisionally accepted
- 1Nanjing University, Nanjing, China
- 2Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University,, suzhou, China
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Peroxisome proliferator-activated receptor gamma (PPAR) is a key target for metabolic disorders that contribute to obesity and type 2 diabetes mellitus (T2DM).However, full agonists such as thiazolidinediones (TZDs) have limitations in terms of side effects. Selective PPAR modulators (SPPARMs) that target alternative binding pockets offer the potential for safer partial agonists. Here, we employed six computational algorithms (Fpocket, DeepSite, CavityPlus, DoGSiteScorer, CASTpFold, POCASA) to identify a novel allosteric pocket (pocket 6-5) in the PPAR ligand-binding domain (LBD), localized at the helix 3 (H3), helix 2 (H2), helix 2' (H2'), and β-sheet interface. A virtual screening of 4,097 natural compounds from traditional Chinese medicine (TCM) libraries was conducted, which led to the identification of ginsenoside Rg5 (TWSZ-5) as a top hit. Molecular docking and molecular dynamics (MD) dynamics revealed TWSZ-5 stabilizes pocket 6-5 through hydrogen bonds with Ser342, Gln345, Lys261, and Lys263. TWSZ-5 promoted beige adipocyte differentiation in adipose-derived stem cells (ADSCs) in vitro, upregulating Ucp1, Prdm16, Cpt1α, and Pgc1α. The present study identifies TWSZ-5 as a novel SPPARM that utilizes an allosteric binding pocket to enhance thermogenesis while mitigating adverse effects. These findings emphasize the potential of TCM derivatives and structure-based screening strategies to develop safer antidiabetic therapies with precision pharmacology.
Keywords: PPAR, Binding pocket, natural product, Virtual Screening, Beige cells
Received: 19 Feb 2025; Accepted: 22 Apr 2025.
Copyright: © 2025 Wang, Shui, Zhang, Chen, Yang, Ji, Shen and Tian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Shiliang Ji, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University,, suzhou, China
Pingping Shen, Nanjing University, Nanjing, China
Qiang Tian, Nanjing University, Nanjing, China
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