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

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).

SUBMITTER: Schuster D

PROVIDER: S-EPMC3254253 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Schuster Daniela D Markt Patrick P Grienke Ulrike U Mihaly-Bison Judit J Binder Markus M Noha Stefan M SM Rollinger Judith M JM Stuppner Hermann H Bochkov Valery N VN Wolber Gerhard G

Bioorganic & medicinal chemistry 20111004 23

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 ...[more]

PMID: 22018919

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