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

Molecular BioSystems
Thangaraj Sindhu, Pappu Srinivasan

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...Continue Reading

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Citations

Oct 19, 2016·Journal of Digestive Diseases·Zhi Qing Yuan, Ke Wei Li
Apr 27, 2019·Expert Opinion on Drug Discovery·Olivia Slater, Maria Kontoyianni
Jul 24, 2018·Journal of Medicinal Chemistry·Ewgenij ProschakDaniel Merk

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