Repurposing FDA-approved drugs as FXR agonists: a structure basedin silicopharmacological study

Abstract

Farnesoid X receptor (FXR) modulates the expression of genes involved in lipid and carbohydrate homeostasis and inflammatory processes. This nuclear receptor is likely a tumor suppressor in several cancers but its molecular mechanism of suppression is still under study. Several studies reported that FXR agonism increase the survival of colorectal, biliary tract and liver cancer patients. In addition, FXR expression was shown to be downregulated in many diseases such as obesity, irritable bowel syndrome, glomerular inflammation, diabetes, proteinuria and ulcerative colitis. Therefore, development of novel FXR agonists may have significant potential in the prevention and treatment of these diseases. In this scenario, computer-aided drug design procedures can be resourcefully applied for the rapid identification of promising drug candidates. In the present research study, we applied the molecular docking method in conjunction with molecular dynamics (MD) simulations to find out potential agonists for FXR based on structural similarity with the drug that is currently used as FXR agonist, obeticholic acid. Our results showed that alvimopan and montelukast could be used as potent FXR activators and outperform the binding affinity of obeticholic acid by forming stable conformation with the protein in silico. However, further investigational studies and validations of the selected drugs are essential to figure out their suitability for in vivo experiments and clinical trials.

Mechanisms Underlying the Protective Effects of Obeticholic Acid-activated FXR in Valproic Acid-induced Hepatotoxicity via Network Pharmacology, Molecular Docking and Molecular Dynamics Simulations

“…And there were no signi cant conformational changes in CYP3A4 and CYP7A1 upon binding with OCA. Notably, the binding energy of OCA-FXR (-7.63 kcal/mol) closely aligns with the previously reported value of -7.6 kcal/mol [40]. Zhang et al observed that OCA improved the hepatic bile acid pro les induced by lipopolysaccharide in pregnant mice, accompanied by the lower expression of bile acid synthase CYP7A1 and the higher expression of CYP3A [41], which was similar to our ndings.…”

Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy

“…However, there is still a long journey ahead. The optimization of concentrations of the compounds, the evaluation of the long-term effects, and the discovery of novel FXR agonists by repurposing FDA-approved drugs might be a promising approach for effectively targeting FXR in cancer [ 216 ]. Considering the fact that FXR and TGR5 are well-characterized receptors of BAs, the application of the dual FXR/TGR5 ligand might be superior to the use of a single agonist [ 217 ].…”

Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment

“…This makes BAs receptors a target for the treatment of liver diseases such as cholestasis, viral hepatitis, liver fibrosis and liver cancer. At present, the FXR agonist obeticholic acid phase III clinical trial results have significant efficacy, and other FXR agonists such as GSK2324 and WAY-362450 have also entered clinical trials and achieved good clinical results (33). Targets for TGR5 are also expected to enter clinical trials in the near future.…”