Abstract/Summary

Over the last few decades, bile acids (BAs) have emerged as important hormone-like signalling molecules. Bile acids have been shown to exert their effects through the binding and activation of the Farnesoid X Receptor (FXR), which regulates various pleiotropic target genes underlying bile acid homeostasis, inflammation and lipid, glucose and cholesterol metabolism. FXR plays a pivotal role in the aetiology of various liver pathologies and metabolic syndromes and, as such, is an attractive therapeutic target. Use of the semi-synthetic BA analogue drug, obeticholic acid (OCA), has been impeded due to its activation of other BA receptors, and due to the promiscuity of systemic FXR activation, which leads to unfavourable and counterintuitive effects. Work described here exploited structural data about the ligand binding domain (LBD) of FXR to design novel, BA-derived agonists. Computational molecular docking approaches were used to determine the putative binding mechanisms of novel compounds, and with supplementary biological activity data, it was postulated that lead candidates implement a unique binding mode. Efforts were devoted to obtaining a 3D structure of the LBD in complex with lead novel compounds and associated cofactors in an effort to validate ligand binding interactions, and to gain further insight into how ligand-mediated structural conformations determine functional activation of FXR. Two lead novel compounds were confirmed as bona fide agonists of FXR, with improved potency compared to OCA, and these were able to recruit coactivators essential for transcriptional activity. Furthermore, these novel agonists were shown to regulate the expression of genes targeted by FXR, both in vitro and in vivo. Taken collectively, the results presented herein suggested that one of the lead compounds may achieve some FXR-target selectivity by its ability to induce conformations of FXR that preferentially recruit specific coactivators. Despite their common BA scaffold, the two lead compounds displayed differential regulation of target genes in vivo compared to OCA and, importantly, this work supports scope for these compounds to be further developed as pharmacological agents for certain diseases.