21-Hydroxy-6,19-epoxyprogesterone: A Promising Therapeutic Agent and a Molecular Tool for Deciphering Glucocorticoid Action

Author(s): Adali Pecci*, Lautaro D. Alvarez, Diego M. Presman, Gerardo Burton*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 18 , Issue 5 , 2018

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Graphical 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.

Keywords: Dissociated ligands, 21-hydroxy-6, 19-epoxyprogesterone, glucocorticoid mechanism of action, glucocorticoid receptor, molecular dynamics, rigid steroids.

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Article Details

Year: 2018
Published on: 14 February, 2018
Page: [428 - 438]
Pages: 11
DOI: 10.2174/1389557516666160118112313
Price: $65

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