Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor
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 activit...
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todo:paper_18607179_v3_n12_p1869_Alvarez2023-10-03T16:33:20Z Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor Álvarez, L.D. Martí, M.A. Veleiro, A.S. Misico, R.I. Estrin, D.A. Pecci, A. Burton, G. Apoptosis Glucocorticoid receptors Molecular dynamics Structure-activity relationships Tissue-specific activity 21 hydroxy 6,19 oxidoprogesterone 21 succinyloxy 6,19 epoxyprogesterone 21-hydroxy-6,19-oxidoprogesterone 21-succinyloxy-6,19-epoxyprogesterone drug derivative gestagen glucocorticoid receptor progesterone animal apoptosis article cell strain COS1 Cercopithecus chemistry computer simulation dimerization drug potentiation human mouse reporter gene structure activity relation Animals Apoptosis Cercopithecus aethiops Computer Simulation COS Cells Dimerization Genes, Reporter Humans Mice Progesterone Progestins Receptors, Glucocorticoid Structure-Activity Relationship 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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA. Fil:Álvarez, L.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_18607179_v3_n12_p1869_Alvarez |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Apoptosis Glucocorticoid receptors Molecular dynamics Structure-activity relationships Tissue-specific activity 21 hydroxy 6,19 oxidoprogesterone 21 succinyloxy 6,19 epoxyprogesterone 21-hydroxy-6,19-oxidoprogesterone 21-succinyloxy-6,19-epoxyprogesterone drug derivative gestagen glucocorticoid receptor progesterone animal apoptosis article cell strain COS1 Cercopithecus chemistry computer simulation dimerization drug potentiation human mouse reporter gene structure activity relation Animals Apoptosis Cercopithecus aethiops Computer Simulation COS Cells Dimerization Genes, Reporter Humans Mice Progesterone Progestins Receptors, Glucocorticoid Structure-Activity Relationship |
| spellingShingle |
Apoptosis Glucocorticoid receptors Molecular dynamics Structure-activity relationships Tissue-specific activity 21 hydroxy 6,19 oxidoprogesterone 21 succinyloxy 6,19 epoxyprogesterone 21-hydroxy-6,19-oxidoprogesterone 21-succinyloxy-6,19-epoxyprogesterone drug derivative gestagen glucocorticoid receptor progesterone animal apoptosis article cell strain COS1 Cercopithecus chemistry computer simulation dimerization drug potentiation human mouse reporter gene structure activity relation Animals Apoptosis Cercopithecus aethiops Computer Simulation COS Cells Dimerization Genes, Reporter Humans Mice Progesterone Progestins Receptors, Glucocorticoid Structure-Activity Relationship Álvarez, L.D. Martí, M.A. Veleiro, A.S. Misico, R.I. Estrin, D.A. Pecci, A. Burton, G. Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor |
| topic_facet |
Apoptosis Glucocorticoid receptors Molecular dynamics Structure-activity relationships Tissue-specific activity 21 hydroxy 6,19 oxidoprogesterone 21 succinyloxy 6,19 epoxyprogesterone 21-hydroxy-6,19-oxidoprogesterone 21-succinyloxy-6,19-epoxyprogesterone drug derivative gestagen glucocorticoid receptor progesterone animal apoptosis article cell strain COS1 Cercopithecus chemistry computer simulation dimerization drug potentiation human mouse reporter gene structure activity relation Animals Apoptosis Cercopithecus aethiops Computer Simulation COS Cells Dimerization Genes, Reporter Humans Mice Progesterone Progestins Receptors, Glucocorticoid Structure-Activity Relationship |
| description |
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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA. |
| format |
JOUR |
| author |
Álvarez, L.D. Martí, M.A. Veleiro, A.S. Misico, R.I. Estrin, D.A. Pecci, A. Burton, G. |
| author_facet |
Álvarez, L.D. Martí, M.A. Veleiro, A.S. Misico, R.I. Estrin, D.A. Pecci, A. Burton, G. |
| author_sort |
Álvarez, L.D. |
| title |
Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor |
| title_short |
Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor |
| title_full |
Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor |
| title_fullStr |
Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor |
| title_full_unstemmed |
Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor |
| title_sort |
hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: a tissue-specific modulator of the glucocorticoid receptor |
| url |
http://hdl.handle.net/20.500.12110/paper_18607179_v3_n12_p1869_Alvarez |
| work_keys_str_mv |
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| _version_ |
1782028396950192128 |