4 research outputs found
Interference of Boswellic Acids with the Ligand Binding Domain of the Glucocorticoid Receptor
Boswellic acids (BAs) possess anti-inflammatory
properties in various
biological models with similar features to those of glucocorticoids
(GCs), such as suppression of the release of pro-inflammatory cytokines.
Hence, the molecular mechanism of BAs responsible for their anti-inflammatory
features might be attributable to interference with the human glucocorticoid
receptor (GR). Due to obvious structural similarities with GCs, we
conducted pharmacophore studies as well as molecular docking simulations
of BAs as putative ligands at the ligand binding site (LBS) of the
GR in distinct functional states. In order to verify receptor binding
and functional activation of the GR by BAs, radiometric binding assays
as well as GR response element-dependent luciferase reporter assay
were performed with dexamethasone (DEX) as a functional positive control.
With respect to the observed position of GCs in GR crystal complexes
in the active antagonist state, BAs docked in a flipped orientation
with estimated binding constants reflecting nanomolar affinities.
For validation, DEX and other steroids were successfully redocked
into their crystal poses in similar ranges as reported in the literature.
In line with the pharmacophore and docking models, the BAs were strong
GR binders (radiometric binding assay), albeit none of the BAs activated
the GR in the reporter gene assay, when compared to the GC agonist
DEX. The flipped scaffolds of all BAs dislodge the known C-11 function
from its receiving amino acid (Asn564), which may explain the silencing
effects of receptor-bound BAs in the reporter gene assay. Together,
our results constitute a compelling example of rigid keys acting in
an adaptable lock qualifying as a reversed induced fit mechanism,
thereby extending the hitherto published knowledge about molecular
target interactions of BAs