21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action
Glucocorticoids are steroid hormones that exert most of their effects through their binding to the glucocorticoid receptor (GR), a ligand regulated transcription factor. Although glucocorticoids are widely used in the clinic, their usage in chronic therapies provokes severe adverse reactions. In the...
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paper:paper_13895575_v16_n_p_Pecci2023-06-08T16:13:10Z 21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action Pecci, Adali Presman, Diego Martín Burton, Gerardo 21-hydroxy-6,19-epoxyprogesterone Dissociated ligands Glucocorticoid mechanism of action Glucocorticoid receptor Molecular dynamics Rigid steroids 21 hydroxy 6 19 epoxyprogesterone dexamethasone glucocorticoid mifepristone paclitaxel progesterone derivative unclassified drug 21-hydroxy-6,19-oxidoprogesterone glucocorticoid glucocorticoid receptor immunosuppressive agent nonsteroid antiinflammatory agent progesterone anxiety apoptosis biological activity breast cancer conformational transition crystal structure depression dimerization gene expression gene overexpression hydrogen bond hypertension immunosurveillance inflammation ligand binding lung cancer molecular biology molecular docking molecular dynamics oligomerization point mutation protein interaction Review spectroscopy therapy effect X ray crystallography analogs and derivatives chemical structure chemistry human metabolism molecular model Anti-Inflammatory Agents, Non-Steroidal Glucocorticoids Humans Immunosuppressive Agents Models, Molecular Molecular Structure Progesterone Receptors, Glucocorticoid Glucocorticoids are steroid hormones that exert most of their effects through their binding to the glucocorticoid receptor (GR), a ligand regulated transcription factor. Although glucocorticoids are widely used in the clinic, their usage in chronic therapies provokes severe adverse reactions. In the quest for safer glucocorticoids a dissociated model was established that proposes a disconnection between GR activated pathways responsible of desired pharmacological effects and pathways involved in adverse GR reactions. Under this model, a myriad of steroidal and non-steroidal compounds has been characterized, with most of them still producing side effects. X-ray crystallographic studies followed by molecular dynamics analysis led research to insights on the receptor Ligand Binding Domain (LBD), which undergoes specific ligand dependent conformational changes that influence receptor activities. In this sense, the flexibility of the ligand structure would contribute to the final GR outcome. Here, we review different data of 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP), a rigid steroid with potential pharmaceutical interest due to its anti-inflammatory and immunosuppressive activities, lacking several GR adverse reactions. The rigid structure endows this compound with an enhanced selectivity towards GR. Molecular characterization of the GR/21OH-6,19OP complex revealed specific intermediate conformations adopted by the receptor that would explain the influence on GR dimerization and the recruitment of a specific set of GR transcription modulators. We summarize recent data that will contribute to understand the complexity of glucocorticoid response. © 2016 Bentham Science Publishers. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Presman, D.M. 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. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13895575_v16_n_p_Pecci http://hdl.handle.net/20.500.12110/paper_13895575_v16_n_p_Pecci |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
21-hydroxy-6,19-epoxyprogesterone Dissociated ligands Glucocorticoid mechanism of action Glucocorticoid receptor Molecular dynamics Rigid steroids 21 hydroxy 6 19 epoxyprogesterone dexamethasone glucocorticoid mifepristone paclitaxel progesterone derivative unclassified drug 21-hydroxy-6,19-oxidoprogesterone glucocorticoid glucocorticoid receptor immunosuppressive agent nonsteroid antiinflammatory agent progesterone anxiety apoptosis biological activity breast cancer conformational transition crystal structure depression dimerization gene expression gene overexpression hydrogen bond hypertension immunosurveillance inflammation ligand binding lung cancer molecular biology molecular docking molecular dynamics oligomerization point mutation protein interaction Review spectroscopy therapy effect X ray crystallography analogs and derivatives chemical structure chemistry human metabolism molecular model Anti-Inflammatory Agents, Non-Steroidal Glucocorticoids Humans Immunosuppressive Agents Models, Molecular Molecular Structure Progesterone Receptors, Glucocorticoid |
| spellingShingle |
21-hydroxy-6,19-epoxyprogesterone Dissociated ligands Glucocorticoid mechanism of action Glucocorticoid receptor Molecular dynamics Rigid steroids 21 hydroxy 6 19 epoxyprogesterone dexamethasone glucocorticoid mifepristone paclitaxel progesterone derivative unclassified drug 21-hydroxy-6,19-oxidoprogesterone glucocorticoid glucocorticoid receptor immunosuppressive agent nonsteroid antiinflammatory agent progesterone anxiety apoptosis biological activity breast cancer conformational transition crystal structure depression dimerization gene expression gene overexpression hydrogen bond hypertension immunosurveillance inflammation ligand binding lung cancer molecular biology molecular docking molecular dynamics oligomerization point mutation protein interaction Review spectroscopy therapy effect X ray crystallography analogs and derivatives chemical structure chemistry human metabolism molecular model Anti-Inflammatory Agents, Non-Steroidal Glucocorticoids Humans Immunosuppressive Agents Models, Molecular Molecular Structure Progesterone Receptors, Glucocorticoid Pecci, Adali Presman, Diego Martín Burton, Gerardo 21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| topic_facet |
21-hydroxy-6,19-epoxyprogesterone Dissociated ligands Glucocorticoid mechanism of action Glucocorticoid receptor Molecular dynamics Rigid steroids 21 hydroxy 6 19 epoxyprogesterone dexamethasone glucocorticoid mifepristone paclitaxel progesterone derivative unclassified drug 21-hydroxy-6,19-oxidoprogesterone glucocorticoid glucocorticoid receptor immunosuppressive agent nonsteroid antiinflammatory agent progesterone anxiety apoptosis biological activity breast cancer conformational transition crystal structure depression dimerization gene expression gene overexpression hydrogen bond hypertension immunosurveillance inflammation ligand binding lung cancer molecular biology molecular docking molecular dynamics oligomerization point mutation protein interaction Review spectroscopy therapy effect X ray crystallography analogs and derivatives chemical structure chemistry human metabolism molecular model Anti-Inflammatory Agents, Non-Steroidal Glucocorticoids Humans Immunosuppressive Agents Models, Molecular Molecular Structure Progesterone Receptors, Glucocorticoid |
| description |
Glucocorticoids are steroid hormones that exert most of their effects through their binding to the glucocorticoid receptor (GR), a ligand regulated transcription factor. Although glucocorticoids are widely used in the clinic, their usage in chronic therapies provokes severe adverse reactions. In the quest for safer glucocorticoids a dissociated model was established that proposes a disconnection between GR activated pathways responsible of desired pharmacological effects and pathways involved in adverse GR reactions. Under this model, a myriad of steroidal and non-steroidal compounds has been characterized, with most of them still producing side effects. X-ray crystallographic studies followed by molecular dynamics analysis led research to insights on the receptor Ligand Binding Domain (LBD), which undergoes specific ligand dependent conformational changes that influence receptor activities. In this sense, the flexibility of the ligand structure would contribute to the final GR outcome. Here, we review different data of 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP), a rigid steroid with potential pharmaceutical interest due to its anti-inflammatory and immunosuppressive activities, lacking several GR adverse reactions. The rigid structure endows this compound with an enhanced selectivity towards GR. Molecular characterization of the GR/21OH-6,19OP complex revealed specific intermediate conformations adopted by the receptor that would explain the influence on GR dimerization and the recruitment of a specific set of GR transcription modulators. We summarize recent data that will contribute to understand the complexity of glucocorticoid response. © 2016 Bentham Science Publishers. |
| author |
Pecci, Adali Presman, Diego Martín Burton, Gerardo |
| author_facet |
Pecci, Adali Presman, Diego Martín Burton, Gerardo |
| author_sort |
Pecci, Adali |
| title |
21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| title_short |
21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| title_full |
21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| title_fullStr |
21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| title_full_unstemmed |
21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| title_sort |
21-hydroxy-6,19-epoxyprogesterone: a promising therapeutic agent and a molecular tool for deciphering glucocorticoid action |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13895575_v16_n_p_Pecci http://hdl.handle.net/20.500.12110/paper_13895575_v16_n_p_Pecci |
| work_keys_str_mv |
AT pecciadali 21hydroxy619epoxyprogesteroneapromisingtherapeuticagentandamoleculartoolfordecipheringglucocorticoidaction AT presmandiegomartin 21hydroxy619epoxyprogesteroneapromisingtherapeuticagentandamoleculartoolfordecipheringglucocorticoidaction AT burtongerardo 21hydroxy619epoxyprogesteroneapromisingtherapeuticagentandamoleculartoolfordecipheringglucocorticoidaction |
| _version_ |
1768546737308303360 |