2. Academic Validation
  3. Structure-based screening, optimization and biological evaluation of novel chrysin-based derivatives as selective PPARγ modulators for the treatment of T2DM and hepatic steatosis

Structure-based screening, optimization and biological evaluation of novel chrysin-based derivatives as selective PPARγ modulators for the treatment of T2DM and hepatic steatosis

  • Eur J Med Chem. 2024 Oct 5:276:116728. doi: 10.1016/j.ejmech.2024.116728.
Lei Ma 1,  Junyuan Tang 2,  Fangyuan Chen 1,  Qingmei Liu 1,  Junjun Huang 1,  Xiawen Liu 3,  Zhi Zhou 4,  Wei Yi 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
  • 2 Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China; Department of Food and Chemical Engineering, Shaoyang University, Shao Shui Xi Road, Shaoyang, 422100, China.
  • 3 Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. Electronic address: lxwgzhmu@gzhmu.edu.cn.
  • 4 Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. Electronic address: zhouzhi@gzhmu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. Electronic address: yiwei@gzhmu.edu.cn.
PMID: 39089002 DOI: 10.1016/j.ejmech.2024.116728
Abstract

In consideration of several serious side effects induced by the classical AF-2 involved "lock" mechanism, recently disclosed PPARγ-Ser273 phosphorylation mode of action has become an alternative and mainstream mechanism for currently PPARγ-based drug discovery and development with an improved therapeutic index. In this study, by virtue of structure-based virtual high throughput screening (SB-VHTS), structurally chemical optimization by targeting the inhibition of the PPARγ-Ser273 phosphorylation as well as in vitro biological evaluation, which led to the final identification of a chrysin-based potential hit (YGT-31) as a novel selective PPARγ Modulator with potent binding affinity and partial agonism. Further in vivo evaluation demonstrated that YGT-31 possessed potent glucose-lowering and relieved hepatic steatosis effects without involving the TZD-associated side effects. Mechanistically, YGT-31 presented such desired therapeutic index, mainly because it effectively inhibited the CDK5-mediated PPARγ-Ser273 phosphorylation, selectively elevated the level of Insulin sensitivity-related GLUT4 and Adiponectin but decreased the expression of insulin-resistance-associated genes PTP1B and SOCS3 as well as inflammation-linked genes IL-6, IL-1β and TNFα. Finally, the molecular docking study was also conducted to uncover an interesting hydrogen-bonding network of YGT-31 with PPARγ-Ser273 phosphorylation-related key residues Ser342 and Glu343, which not only gave a clear verification for our targeting modification but also provided a proof of concept for the abovementioned molecular mechanism.

Keywords

Chrysin-based derivatives; Hepatic steatosis; PPARγ-Ser273 phosphorylation; Selective PPARγ modulator; Structure-based virtual screening; T2DM.

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