Rational ligand-based virtual screening and structure–activity relationship studies in the ligand-binding domain of the glucocorticoid receptor-α

2009 ◽  
Vol 1 (3) ◽  
pp. 483-499 ◽  
Author(s):  
Valeria Onnis ◽  
Gemma K Kinsella ◽  
Giorgio Carta ◽  
Darren Fayne ◽  
David G Lloyd
Keyword(s):  
Virtual Screening ◽  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Activity Relationship ◽  
Structure Activity

scholarly journals Folding and stability of the ligand-binding domain of the glucocorticoid receptor

2002 ◽  
Vol 11 (8) ◽  
pp. 1926-1936 ◽  
Author(s):  
Stephen H. McLaughlin ◽  
Sophie E. Jackson
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain

scholarly journals Molecular Determinants of Glucocorticoid Receptor Mobility in Living Cells: the Importance of Ligand Affinity

2003 ◽  
Vol 23 (6) ◽  
pp. 1922-1934 ◽  
Author(s):  
Marcel J. M. Schaaf ◽  
John A. Cidlowski
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Conformational Change ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Dependent Manner ◽  
Dna Binding Domain ◽  
Ligand Affinity ◽  
High Affinity

ABSTRACT The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), which is activated upon ligand binding, and can alter the expression of target genes either by transrepression or transactivation. We have applied FRAP (fluorescence recovery after photobleaching) to quantitatively assess the mobility of the yellow fluorescent protein (YFP)-tagged human GR α-isoform (hGRα) in the nucleus of transiently transfected COS-1 cells and to elucidate determinants of its mobility. Addition of the high-affinity agonist dexamethasone markedly decreases the mobility of the receptor in a concentration-dependent manner, whereas low-affinity ligands like corticosterone decrease the mobility to a much lesser extent. Analysis of other hGRα ligands differing in affinity suggests that it is the affinity of the ligand that is a major determinant of the decrease in mobility. Similar results were observed for two hGRα antagonists, the low-affinity antagonist ZK98299 and the high-affinity antagonist RU486. The effect of ligand affinity on mobility was confirmed with the hGRα mutant Q642V, which has an altered affinity for triamcinolone acetonide, dexamethasone, and corticosterone. Analysis of hGRα deletion mutants indicates that both the DNA-binding domain and the ligand-binding domain of the receptor are required for a maximal ligand-induced decrease in receptor mobility. Interestingly, the mobility of transfected hGRα differs among cell types. Finally, the proteasome inhibitor MG132 immobilizes a subpopulation of unliganded receptors, via a mechanism requiring the DNA-binding domain and the N-terminal part of the ligand-binding domain. Ligand binding makes the GR resistant to the immobilizing effect of MG132, and this effect depends on the affinity of the ligand. Our data suggest that ligand binding induces a conformational change of the receptor which is dependent on the affinity of the ligand. This altered conformation decreases the mobility of the receptor, probably by targeting the receptor to relatively immobile nuclear domains with which it transiently associates. In addition, this conformational change blocks immobilization of the receptor by MG132.

Structure–activity relationship of novel DAPK inhibitors identified by structure-based virtual screening

2010 ◽  
Vol 18 (7) ◽  
pp. 2728-2734 ◽  
Author(s):  
Masako Okamoto ◽  
Kiyoshi Takayama ◽  
Tomoko Shimizu ◽  
Ayumu Muroya ◽  
Toshio Furuya
Keyword(s):  
Virtual Screening ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Of

Enhancing the Stability and Solubility of the Glucocorticoid Receptor Ligand-Binding Domain by High-Throughput Library Screening

2010 ◽  
Vol 403 (4) ◽  
pp. 562-577 ◽  
Author(s):  
Tobias Seitz ◽  
Ralf Thoma ◽  
Guillaume A. Schoch ◽  
Martine Stihle ◽  
Jörg Benz ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
High Throughput ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Library Screening ◽  
Receptor Ligand ◽  
The Stability

scholarly journals Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors

2018 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Rachel J. Harding ◽  
Ivan Franzoni ◽  
Mani Ravichandran ◽  
Mandeep K. Mann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zinc Finger ◽  
Proteasome Inhibitors ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Activity Relationship ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

AbstractHDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation, and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of a HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155 are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens-up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

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