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

• Published in: European journal of medicinal chemistry 2024-10, Vol.276, p.116728, Article 116728
• Main Authors: Ma, Lei, Tang, Junyuan, Chen, Fangyuan, Liu, Qingmei, Huang, Junjun, Liu, Xiawen, Zhou, Zhi, Yi, Wei
• Format: Article
• Language: English
• Subjects: Animals; Chrysin-based derivatives; Diabetes Mellitus, Type 2 - drug therapy; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fatty Liver - drug therapy; Fatty Liver - metabolism; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; Hepatic steatosis; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Male; Mice; Molecular Docking Simulation; Molecular Structure; PPAR gamma - agonists; PPAR gamma - metabolism; PPARγ-Ser273 phosphorylation; Selective PPARγ modulator; Structure-Activity Relationship; Structure-based virtual screening; T2DM
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116728

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. Through structure-based virtual high throughput screening, chemical modification by targeting the inhibition of the PPARγ-Ser273 phosphorylation as well as in vitro and in vivo biological evaluation, chrysin-derived YGT-31 is developed herein as a new and potent selective PPARγ modulator for the treatment of T2DM and hepatic steatosis. [Display omitted] •YGT-31 derived from chrysin was identified as the new and potent SPPARγM.•Potent anti-T2DM and anti-hepatic steatosis effect of YGT-31 was demonstrated.•YGT-31 up-regulated the expression of Glut4 and adiponectin selectively.•The PPARγ-Ser273 phosphorylation level, PTP1B and SOCS were effectively inhibited.•YGT-31 demonstrated an interesting hydrogen-bonding network with PPARγ LBD.