Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation.
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).
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
Daniela
D
Schuster
Patrick
P
Markt
Ulrike
U
Grienke
Judit
J
Mihaly-Bison
Markus
M
Binder
Stefan M
SM
Noha
Judith M
JM
Rollinger
Hermann
H
Stuppner
Valery N
VN
Bochkov
Gerhard
G
Wolber
D001665:Binding Sites; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated