Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

Abstract

Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes. Agonists of both the bile acid receptors increase insulin sensitivity and control glucose, lipids and bile acid homeostasis. The current study deals with the identification of novel dual agonists using ligand and structure-based virtual screening. Initially, an experimentally proven well-known dual agonist of FXR and TGR5, namely INT-767, was docked into the binding sites of FXR and TGR5 to determine the protein residues important for ligand binding. The docked complexes FXRINT-767 and TGR5INT-767 were used to generate e-pharmacophore hypotheses. Ligand-based virtual screening was carried out using the hypothetical e-pharmacophore model against the ChemBridge database. Further, structure-based virtual screening was performed with screened hits to find potential agonists of FXR and TGR5. A total of four best agonists were identified based on their affinity and mode of interactions with the receptors. The binding mode of these compounds with both receptors was analyzed in detail. Furthermore, molecular dynamics, ADME toxicity prediction, density functional theory and binding free energy calculations were carried out to rank the compounds. Based on the above analyses, the most potent compound, ChemBridge_9149693, was selected for further in vitro studies. The results of in vitro assays suggested that ChemBridge_9149693 is a potent and promising drug for the treatment of type II diabetes. Thus, the compound could be used for further drug design and development of dual agonists of FXR and TGR5.

Identification of key amino acid residues in the hTGR5–nomilin interaction and construction of its binding model

“…Recently, in silico methods such as pharmacophore modelling and molecular dynamics simulation have rapidly advanced, enabling fast and easy screening for identifying new GPCR agonists and antagonists. Indeed, some TGR5 agonists were identified using pharmacophore modeling [ 28 , 29 ]. However, structural information on TGR5–ligand interaction is insufficient for highly accurate in silico screening, causing low predictive power.…”

Role of farnesoid X receptor in cholestasis

“…103 In addition, several pharmacological researches have focused on the identification of dual agonists of FXR and TGR5. 104,105 FXR antagonists, however, may also have a liver-protective function in cholestatic diseases.…”

“…One study demonstrated that the potent FXR/TGR5 agonist INT‐767 repressed hepatic inflammation and biliary fibrosis in Mdr 2 −/− mice by decreasing endogenous bile acid output and increasing bicorbonate output . In addition, several pharmacological researches have focused on the identification of dual agonists of FXR and TGR5 . FXR antagonists, however, may also have a liver‐protective function in cholestatic diseases.…”

Comprehensivein silicomodeling of the rice plant PRR Xa21 and its interaction with RaxX21-sY and OsSERK2

“…Only about 2% of all membrane bound proteins have been crystallized and the information added to the protein data bank (PDB). 33 Also, no crystallographic structure of entire plant PRRs are available in the PDB to date, only partial structures are available (such as LRRs or kinase domains). As Xa21 is a membrane bound PRR with a complicated fourcomponent conguration, no structure of Xa21 has yet been determined experimentally, therefore in silico modeling approaches were implemented to predict a structural model of Xa21.…”