DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators.
In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development.
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
Pascal
P
Heitel
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
Janosch
J
Achenbach
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
Daniel
D
Moser
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
Ewgenij
E
Proschak
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany. Electronic address: merk@pharmchem.uni-frankfurt.de.
Daniel
D
Merk
D000077556:Alitretinoin; D000818:Animals; D000077610:Bexarotene; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D000071518:Liver X Receptors / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D000071518:Liver X Receptors; D013764:Tetrahydronaphthalenes; D000077556:Alitretinoin; D014212:Tretinoin; D000077610:Bexarotene
Alitretinoin; Bexarotene; Liver X receptor; Nuclear receptors; SOSA