The G-protein coupled bile acid receptor 1 (GPBAR1 or TGR5) is the major cell membrane receptor for bile acids regulating metabolic and immunological functions. Its pharmacological modulation has been shown to alleviate inflammatory diseases, such as type 2 diabetes and atherosclerosis. The naturally occurring lignan leoligin and structural analogues have shown anti-inflammatory effects in vitro. However, the underlying molecular targets are still unknown. In this study, we identify the natural product-inspired synthetic structural analogue of leoligin, LT-188A (1), as a novel nonsteroidal TGR5 agonist. LT-188A (1) induced cyclic adenosine monophosphate (cAMP) accumulation and cAMP response element (CRE)-dependent luciferase activity in a concentration- and TGR5-dependent manner. Consistently, LT-188A (1) inhibited activation of the pro-inflammatory transcription factor nuclear factor κB (NFκB) only in TGR5 expressing cells. In macrophages, LT-188A (1) reduced the expression levels of pro-inflammatory cytokines and the production of nitric oxide (NO) as determined by qPCR and the Griess assay, respectively. We showed that LT-188A (1) decreased the levels of production of these inflammatory mediators in macrophages. In conclusion, we demonstrate that LT-188A (1) is a novel natural product-inspired TGR5 agonist with promising anti-inflammatory in vitro bioactivity in relevant cellular assays representing a promising tool compound with potential for further development.

2023-12-29·Journal of biomolecular structure & dynamics

Identification of potential drug candidates as TGR5 agonist to combat type II diabetes using in silico docking and molecular dynamics simulation studies

Article

作者: Shrivastava, Ashish ; Lokhande, Kiran Bharat ; Bhimanwar, Rachana S. ; Mittal, Amit ; Singh, Ashutosh ; Chitlange, Sohan S.

A cell surface bile acid receptor TGR5 being considered as a novel target for Type II diabetes found to be expressed in various tissues. A major role for TGR5 is to maintain blood sugar levels and increase in energy expenditure. These benefits make it a potential candidate for the treatment of type 2 diabetes, obesity and other metabolic disorder. To date, many novel TGR5 agonists have been synthesized and evaluated in the literature, but very few in silico computational studies have been reported. The discovery of a high-resolution crystal structure of TGR5 in 2020 provides an excellent opportunity for computational screening of potential agonists. In this study, we, therefore, aim to search novel, less toxic TGR5 agonists by iteratively analyzing molecular docking against TGR5 (PDB ID: 7CFN) by means of structure-based virtual screening. The docking score of the designed coumarin derivatives that have been docked successfully varies between -9.4 and -9.0 kcal/mol. The molecular docking and ADMET profile examinations of compounds D1, D5 and D15 revealed that these have a strong affinity for the active site residues of TGR5. In addition, molecular dynamics simulation (MDS) studies have shown the stability of compounds that bind to TGR5. It can be summarized that designed coumarin derivatives seem to have promising activity as TGR5 agonists.Communicated by Ramaswamy H. Sarma.

2023-11-01·Molecular nutrition & food research

Curcumin Compensates GLP‐1 Deficiency via the Microbiota‐Bile Acids Axis and Modulation in Functional Crosstalk between TGR5 and FXR in ob/ob Mice

Article

作者: Tian, Fengyuan ; Huang, Qi ; Feng, Xiaohong ; Fan, Yichang ; Chen, Jie ; Chen, Tianxi ; Xu, Wangda

Scope:

Glucagon‐like peptide‐1 (GLP‐1) deficiency occurs in obesity‐related pathologies due to defects in the intestinal lumen. And expanding the L‐cell population has emerged as a promising avenue to elevate GLP‐1 secretion to tackle metabolic disorders. Curcumin (Cur), the principal active component of spice turmeric, possesses well‐established anti‐obesity properties. To clarify, the study investigates whether Cur promotes GLP‐1 secretion built upon the L‐cell expansion.

Methods and results:

Cur (60 mg kg−1) is administered orally to male ob/ob mice for 8 weeks. Cur ameliorates obesity and impaires glucose tolerance through increasing energy expenditure in ob/ob mice, accompanied by the maintenance of crypt architecture and gut permeability. It refines the microbial structure and bile acid (BA) profiles, resulting in deoxycholic acid (DCA) accumulation by weakening the enrichment of Lactobacillus. Further analyses show radically different properties of Cur on the intestine function of TGR5 and FXR (i.e., activation and repression). Cur amplifies L‐cell number to promote GLP‐1 secretion in ob/ob mice.

Conclusions:

The findings suggest that Cur may act as a natural TGR5 agonist and FXR antagonist to improve obesity by enhancing GLP‐1 release from L‐cell expansion via the gut microbiota‐BAs‐TGR5/FXR axis, and it may serve as a promising therapeutic agent to compensate obesity‐related metabolic disorders.

100 项与 TGR5 agonist(Intercept Pharmaceuticals/Servier) 相关的药物交易

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