Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking

Farnesol X receptor (FXR) is a member of the metabolic nuclear receptor (NR) superfamily of regulatory proteins. FXR was recognized to be a transcriptional sensor for bile acids, and now it has been shown that activating FXR has important roles in controlling bile acid homeostasis, lipoprotein and glucose metabolism, and hepatic regeneration. For the sake of discovering new, potent non-steroidal FXR ligands, we have established a virtual screening workflow by using Phase Shape and induced fit docking (IFD). Phase shape was performed based on a combination of shape-only and atom types or pharmacophore modes. The results indicated that the pharmacophore mode yielded the best result for our system. The best receptor model was chosen by evaluating the cross-IFD models induced by three crystal structures 3DCT, 3FLI and 3OKI. The Enamine database was screened by the proposed workflow and 50 molecules were selected and purchased for bioassays. Among them, two compounds were found to be the new, potent FXR ligands in cell-based assay. (C) 2012 Elsevier Ltd. All rights reserved.