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Abstract:

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.

Registro:

Documento: Artículo
Título:21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action
Autor:Pecci, A.; Alvarez, L.D.; Presman, D.M.; Burton, G.
Filiación:Dpto. Química Biológica/IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
Dpto. Química Orgánica/UMYMFOR-CONICET, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute NIH, Bethesda, United States
Palabras clave: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
Año:2016
Volumen:16
DOI: http://dx.doi.org/10.2174/1389557516666160118112313
Título revista:Mini-Reviews in Medicinal Chemistry
Título revista abreviado:Mini-Rev. Med. Chem.
ISSN:13895575
CODEN:MMCIA
CAS:dexamethasone, 50-02-2; mifepristone, 84371-65-3; paclitaxel, 33069-62-4; progesterone, 57-83-0; 21-hydroxy-6,19-oxidoprogesterone; Anti-Inflammatory Agents, Non-Steroidal; Glucocorticoids; Immunosuppressive Agents; Progesterone; Receptors, Glucocorticoid
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13895575_v16_n_p_Pecci

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Citas:

---------- APA ----------
Pecci, A., Alvarez, L.D., Presman, D.M. & Burton, G. (2016) . 21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action. Mini-Reviews in Medicinal Chemistry, 16.
http://dx.doi.org/10.2174/1389557516666160118112313
---------- CHICAGO ----------
Pecci, A., Alvarez, L.D., Presman, D.M., Burton, G. "21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action" . Mini-Reviews in Medicinal Chemistry 16 (2016).
http://dx.doi.org/10.2174/1389557516666160118112313
---------- MLA ----------
Pecci, A., Alvarez, L.D., Presman, D.M., Burton, G. "21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action" . Mini-Reviews in Medicinal Chemistry, vol. 16, 2016.
http://dx.doi.org/10.2174/1389557516666160118112313
---------- VANCOUVER ----------
Pecci, A., Alvarez, L.D., Presman, D.M., Burton, G. 21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action. Mini-Rev. Med. Chem. 2016;16.
http://dx.doi.org/10.2174/1389557516666160118112313