Exploring the Molecular Basis of Action of the Passive Antiglucocorticoid 21-Hydroxy-6,19-epoxyprogesterone

L.D. ALVAREZ; M.A. MARTI; A.S. VELEIRO; D.M. PRESMAN; D.A. ESTRIN; A. PECCI; G. BURTON

JOURNAL OF MEDICINAL CHEMISTRY

American Chemical Society

Lugar: Columbus, OH; Año: 2008 vol. 51 p. 1352 - 1360

0022-2623

21-Hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a selective antiglucocorticoid that lacks the bulkysubstituent at C-11 found in active antagonists of the glucocorticoid receptor (GR). Ligand-free GR ligand-binding domain (LBD) and GR LBD complexed with 21OH-6,19OP or the agonist dexamethasone weresimulated during 6 ns using molecular dynamics. Results suggest that the time fluctuation and averageposition adopted by the H1-H3 loop affect the ability of GR LBD-21OH-6,19OP complex to homodimerize,a necessary step in transcriptome assembly. A nuclear localization and a transactivation experiment showedthat, although 21OH-6,19OP activates the translocation of the GR, the nuclear complex is unable to inducethe transcription of a reporter driven by a promoter, that requires binding to a GR homodimer to be activated.These findings support the hypothesis that the passive antagonist mode of action of 21OH-6,19OP resides,at least in part, in the incapacity of the GR-21OH-6,19OP complex to dimerize.