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Hemisuccinate of 21‐Hydroxy‐6,19‐Epoxyprogesterone: A Tissue‐Specific Modulator of the Glucocorticoid Receptor

2008; Wiley; Volume: 3; Issue: 12 Linguagem: Inglês

10.1002/cmdc.200800256

1860-7187

Lautaro D. Álvarez, Marcelo A. Martí, Adriana S. Veleiro, Rosana I. Misico, Darío A. Estrı́n, Adalı́ Pecci, Gerardo Burton,

Steroid Chemistry and Biochemistry

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.