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.