2 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
Tetra- and Pentacyclic Triterpene Acids from the Ancient Anti-inflammatory Remedy Frankincense as Inhibitors of Microsomal Prostaglandin E<sub>2</sub> Synthase‑1
The microsomal prostaglandin E<sub>2</sub> synthase (mPGES)-1 is
the terminal enzyme in the biosynthesis of prostaglandin (PG)ÂE<sub>2</sub> from cyclooxygenase (COX)-derived PGH<sub>2</sub>. We previously
found that mPGES-1 is inhibited by boswellic acids (IC<sub>50</sub> = 3–30 μM), which are bioactive triterpene acids present
in the anti-inflammatory remedy frankincense. Here we show that besides
boswellic acids, additional known triterpene acids (i.e., tircuallic,
lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1
with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic
acid (<b>6</b>) and 3α-acetoxy-7,24-dienetirucallic acid
(<b>10</b>) inhibited mPGES-1 activity in a cell-free assay
with IC<sub>50</sub> = 0.4 μM, each. Structure–activity
relationship studies and docking simulations revealed concrete structure-related
interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and
-2 were hardly affected by the triterpene acids (IC<sub>50</sub> >
10 μM). Given the crucial role of mPGES-1 in inflammation and
the abundance of highly active triterpene acids in frankincence extracts,
our findings provide further evidence of the anti-inflammatory potential
of frankincense preparations and reveal novel, potent bioactivities
of tirucallic acids, roburic acids, and lupeolic acids