In silico comparative docking of glucocorticoid-related ligands across GR, PR and AR

Abstract This proof-of-concept study used comparative molecular docking to investigate the apparent binding preferences of glucocorticoid-related ligands across the glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR). This cross-receptor design is pharmacologically relevant because steroid receptors share structural and functional features, and steroidal glucocorticoids may show variable binding selectivity across related nuclear receptors. In parallel, selective glucocorticoid receptor modulators (SEGRMs) are designed to alter GR-mediated transcriptional responses in an effort to preserve anti-inflammatory activity while reducing selected adverse effects. The GR model was based on the budesonide-bound ligand-binding domain deposited in the Protein Data Bank under accession code 5NFP.1 The docking protocol was evaluated for each receptor model (GR, PR, and AR) by redocking the reference ligand and calculating the root-mean-square deviation (RMSD) between the top-ranked docked pose and the crystallographic ligand orientation, using the rms_cur command in PyMOL without prior structural alignment. Redocking reproduced the native pose with RMSD values of 0.404 Å for GR, 0.638 Å for PR, and 1.564 Å for AR, all below the commonly used 2.0 Å criterion for successful pose reproduction. Each ligand-receptor pair was docked in triplicate; docking scores are reported as mean ± standard deviation across the three independent runs. Cross-receptor selectivity was expressed as a difference of docking scores (Δ = Score(PR or AR) − Score(GR), in kcal/mol) rather than as a ratio, since docking scores approximate a free-energy quantity on an interval scale without a true zero point, for which a difference is the more defensible comparative metric than a ratio. Docking scores were interpreted as relative, model-dependent estimates of binding favorability rather than direct experimental measures of binding affinity, receptor activation, therapeutic efficacy, or safety. The results are hypothesis-generating and require confirmation through experimental receptor-binding and functional assays.