AI-ACCELERATED DRUG DISCOVERY

Targeting GPCRs for Treating Obesity and Inflammation

Designing dual agonist to CD36/GPR120

AI revolutionizes the drug discovery process

Background

  • GPR120 and CD36 are novel promising targets for obesity treatment by modulating fat taste perception.
  • Agonists of GPR120 and CD36 decrease food consumption.
  • Dual action leads to more pronounced effect.
  • Agonists of GPR120/CD36 are also promising as anti-inflammatory agents.

Methodology

  • The first ever atomistic models of full-scale GPR120 and CD36 proteins in their native membrane environment were built including the PTM.
  • Extensive MD simulations were performed and the ensembles of representative protein conformations were extracted
  • Ensemble docking simulations were performed to study the mechanism of action of prospective fatty acid analogues.
  • Extensive in vitro and in vivo studies on cell lines and murine models were performed.

Results

  • Several highly potent compounds were found from the focused library of fatty acid analogues and confirmed both computationally and experimentally in vitro and in vivo.
  • The NKS3 and NKS5 compounds show high efficacy in weight loss in murine obesity model.
  • The NKS3 and NKS5 are proved to be a dual agonist of both CD36 and GPR120.
  • NKS3 acts in TAB1/TAK1/JNK pathway via GPR120 and reduces inflammation in RAW 264.7 cells, acute lung injury model, kidney and liver inflammation models, septic shock and neuroinflammation models.
  • The project is being processing towards IND stage.
NKS3 decreases the concertation of pro-inflammatory cytokine (A) and enhances the survival rate of LPS-challenged mice (B).
NKS3 decreases the concertation of pro-inflammatory cytokine (A) and enhances the survival rate of LPS-challenged mice (B).