Is Antagonism of E/Z-Guggulsterone at the Farnesoid X Receptor Mediated by a Noncanonical Binding Site? A Molecular Modeling Study

摘要

Guggulsterone 1,the active principle of guggulipid,has been used in ethnic medicine for thousands of years for its antinflammatory and antilipidemic activities.The activities of 1 are apparently mediated by its interaction with an array of nuclear receptors,including endocrine steroid receptors and metabolic lipid receptors.Although relatively weak,the activity at the metabolic farnesoid X receptor(FXR)is particularly intriguing,as 1 is,so far,the only antagonist known for this receptor,with a peculiar ability of gene selective modulation.We report here a systematic study aimed at identifying the potential binding pocket of 1 at FXR.Although 1 could be docked into the canonical binding site,we identified a novel,so far undescribed binding pocket,localized near the loop region between helix 1 and helix 2.This novel binding pocket may explain some of the peculiar characteristics of 1 when acting at FXR.