Glucocorticoid receptor modulators informed by crystallography lead to a new rationale for receptor selectivity,...

Area of Science:

• Pharmacology
• Structural Biology
• Medicinal Chemistry

Background:

• Glucocorticoids are vital for treating inflammation and autoimmune diseases.
• Understanding the structural basis of glucocorticoid receptor (GR) interactions is key to developing improved therapeutics.
• Existing glucocorticoids have limitations, necessitating the search for novel ligands with differentiated profiles.

Purpose of the Study:

• To introduce and characterize a new class of GR ligands, exemplified by Compound 10.
• To elucidate the structural basis of Compound 10's interaction with the GR ligand binding domain (LBD).
• To evaluate the anti-inflammatory potential and selectivity of Compound 10 in preclinical models.

Main Methods:

• Stereospecific synthesis of a novel dibenzoxepane/dibenzosuberane sulfonamide (Compound 10).
• In vitro assays assessing GR selectivity and gene expression profiling.
• In vivo testing in acute and chronic inflammation models.
• X-ray crystallography to determine the GR LBD/Compound 10 complex structure.

Main Results:

• Compound 10 demonstrated potent anti-inflammatory activity in vivo, comparable to prednisolone.
• It exhibited selectivity for the GR over other steroid receptors.
• Compound 10 displayed a differentiated gene expression profile, with lower transactivation and comparable transrepression versus clinical glucocorticoids.
• Crystal structure revealed a novel binding conformation of Compound 10 within the GR LBD, distinct from classical ligand binding modes.

Conclusions:

• Compound 10 represents a new family of GR ligands with significant anti-inflammatory properties.
• Its unique binding conformation provides a novel structural basis for GR interaction, selectivity, and efficacy.
• This work opens new possibilities for structure-based drug design of targeted anti-inflammatory agents.