In silico study of obeticholic acid analogs as Farnesoid X Receptor agonists

Nuclear receptors (NRs) are ligand-activated transcription factors that, in response to lipophilic hormones, vitamins, and dietary lipids, regulate numerous aspects of mammalian physiology, including development, reproduction, and metabolism. Bile acid (BA) receptors represent well-defined targets for the development of novel therapeutic approaches for metabolic and inflammatory diseases. The farnesoid X receptor (FXR) was identified as an orphan steroid receptor-like nuclear receptor in the late 1990s. FXR activation is crucial in many physiological functions of the liver. A vital role of FXR is to influence the amount of bile acids in hepatocytes by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting enterohepatic circulation, thereby protecting hepatocytes from toxic bile acid accumulation. Furthermore, FXR mediates intestinal bile acid biotransformation, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first analyze the mechanisms of the different pleiotropic actions of FXR agonists. FXR activation induces distinctive changes in circulating cholesterol in animal and human models. We present an evaluation of the interaction of various obeticholic acid analogs and other bile salts by studying their binding energies and receptor-ligand interactions with AutoDock software. The results open the possibility of using new alternatives by deriving structures at position 3 of the steroid nucleus.