Targeting GPCRs for Treating Obesity and Inflammation
Designing dual agonist to CD36/GPR120
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).
