Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis
Peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ modulators (SPPARγMs) t...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1579445/full |
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| author | Zhen Wang Kexin Shui Zehui Zhang Yihan Chen Nanfei Yang Shiliang Ji Pingping Shen Qiang Tian Qiang Tian |
| author_facet | Zhen Wang Kexin Shui Zehui Zhang Yihan Chen Nanfei Yang Shiliang Ji Pingping Shen Qiang Tian Qiang Tian |
| author_sort | Zhen Wang |
| collection | DOAJ |
| description | Peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ modulators (SPPARγMs) 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 PPARγ 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 SPPARγM 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. |
| format | Article |
| id | doaj-art-92865a58b22e47a6bcf5e594532b01d9 |
| institution | DOAJ |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj-art-92865a58b22e47a6bcf5e594532b01d92025-08-20T02:57:26ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-05-011310.3389/fchem.2025.15794451579445Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesisZhen Wang0Kexin Shui1Zehui Zhang2Yihan Chen3Nanfei Yang4Shiliang Ji5Pingping Shen6Qiang Tian7Qiang Tian8State Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaSuzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Department of Urology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaPeroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ modulators (SPPARγMs) 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 PPARγ 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 SPPARγM 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.https://www.frontiersin.org/articles/10.3389/fchem.2025.1579445/fullPPARγbinding pocketnatural productvirtual screeningbeige cells |
| spellingShingle | Zhen Wang Kexin Shui Zehui Zhang Yihan Chen Nanfei Yang Shiliang Ji Pingping Shen Qiang Tian Qiang Tian Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis Frontiers in Chemistry PPARγ binding pocket natural product virtual screening beige cells |
| title | Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis |
| title_full | Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis |
| title_fullStr | Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis |
| title_full_unstemmed | Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis |
| title_short | Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis |
| title_sort | discovery of a novel binding pocket in pparγ for partial agonists structure based virtual screening identifies ginsenoside rg5 as a partial agonist promoting beige adipogenesis |
| topic | PPARγ binding pocket natural product virtual screening beige cells |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1579445/full |
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