title: IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING.
abstract: Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR) antagonists among nuclear receptor (NR) ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available "Binding Database". Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2)D3and 25(OH2)D3. The first virtual screen identified 32 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA) are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50value of 15.8 µM. The second screen identified 162 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%), TRα/β ligands (7%) and LxRα/β ligands (7%). The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Teske
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Premchendar
authors.initials: P
authors.lastname: Nandhikonda
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Bogart
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Belaynesh
authors.initials: B
authors.lastname: Feleke
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Preetpal
authors.initials: P
authors.lastname: Sidhu
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Yuan
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Preston
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Goy
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Silvaggi
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Woman and Infant's Hospital of Rhode Island, Alpert Medical School of, Brown University, Provence, RI 02903, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Endocrine Research Unit, Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
keywords: Virtual screening; estrogen receptor; nuclear receptor; thyroid receptor; vitamin D receptor