Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation

Daniela Schuster; Patrick Markt; Ulrike Grienke; Judit Mihaly-Bison; Markus Binder; Stefan M Noha; Judith M Rollinger; Hermann Stuppner; Valery N Bochkov; Gerhard Wolber

doi:10.1016/j.bmc.2011.09.056

Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation

Bioorg Med Chem. 2011 Dec 1;19(23):7168-80. doi: 10.1016/j.bmc.2011.09.056. Epub 2011 Oct 4.

Authors

Daniela Schuster¹, Patrick Markt, Ulrike Grienke, Judit Mihaly-Bison, Markus Binder, Stefan M Noha, Judith M Rollinger, Hermann Stuppner, Valery N Bochkov, Gerhard Wolber

Affiliation

¹ Computer-Aided Molecular Design Group, Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria. Daniela.Schuster@uibk.ac.at

Abstract

The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Drug Design
HEK293 Cells
Humans
Models, Molecular
Receptors, Cytoplasmic and Nuclear / agonists*
Receptors, Cytoplasmic and Nuclear / chemistry
Receptors, Cytoplasmic and Nuclear / metabolism
Structure-Activity Relationship

Substances

Receptors, Cytoplasmic and Nuclear
farnesoid X-activated receptor