IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING. Nucl Receptor Res 2014;1
Date
11/25/2014Pubmed ID
25419525Pubmed Central ID
PMC4240308DOI
10.11131/2014/101076Abstract
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)D3 and 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 IC50 value 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.
Author List
Teske K, Nandhikonda P, Bogart JW, Feleke B, Sidhu P, Yuan N, Preston J, Goy R, Han L, Silvaggi NR, Singh RK, Bikle DD, Cook JM, Arnold LAAuthors
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeJames M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee
Nicholas R. Silvaggi PhD Assistant Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee
