Molecular modelling of the human glucocorticoid receptor (hGR) ligand-binding domain (LBD) by homology with the human estrogen receptor α (hERα) LBD: quantitative structure–activity relationships within a series of CYP3A4 inducers where induction is mediated via hGR involvement

The results of homology modelling of the human glucorticoid receptor (hGR) ligand-binding domain (LBD) based on the ligand-bound domain of the human estrogen receptor α (hERα) are reported. It is shown that known hGR ligands which induce the human cytochrome P450 enzyme CYP3A4 are able to fit the putative ligand-binding site of the nuclear hormone receptor and form hydrogen bonds with key amino acid residues within the binding pocket. Quantitative structure–activity relationships (QSARs) have been derived for hGR-mediated CYP3A4 induction which involve certain molecular structural and physicochemical properties of the ligand themselves, yielding good correlations ( R=0.96–0.98) with fold induction of CYP3A4 known to be mediated via hGR involvement.