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Hemisuccinate of 21‐Hydroxy‐6,19‐Epoxyprogesterone: A Tissue‐Specific Modulator of the Glucocorticoid Receptor
Author(s) -
Álvarez Lautaro D.,
Martí Marcelo A.,
Veleiro Adriana S.,
Misico Rosana I.,
Estrin Darío A.,
Pecci Adalí,
Burton Gerardo
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800256
Subject(s) - transactivation , antiglucocorticoid , glucocorticoid receptor , agonist , chemistry , moiety , receptor , ligand (biochemistry) , biophysics , stereochemistry , biochemistry , biology , transcription factor , gene
Abstract The introduction of a hemisuccinate group at the 21‐position of the passive antiglucocorticoid 21OH‐6,19OP leads to a compound (21HS‐6,19OP) with a notable activity profile toward the glucocorticoid receptor (GR). In contrast to the parent steroid, 21HS‐6,19OP behaves as a pure agonist of GR activity in direct transactivation assays. However, the apoptotic effects of 21HS‐6,19OP show that the effect depends on cell type: while 21HS‐6,19OP is a pure agonist in L929 mouse fibroblasts, in thymocytes 21HS‐6,19OP had significant antiglucocorticoid activity. This tissue‐specific activity makes 21HS‐6,19OP a novel selective GR modulator. To investigate the molecular basis of action of 21HS‐6,19OP, we carried out molecular dynamics simulations (6 ns) of the GR ligand binding domain (LBD) complexed with 21HS‐6,19OP. Our results indicate that the hemisuccinate moiety may play a key role in stabilizing the active conformation of the receptor dimerization interface, reverting the changes observed with the antagonist 21OH‐6,19OP. Other changes in regions of the GR related to cofactor recruitment (possibly tissue‐specific), could explain this particular activity profile.