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VOL. 76 (2), 223-239, 2010 PREDICTION OF LIGAND BINDING ENERGY...

as glycosylated or sulfated derivatives and only as phenolic
acid derivatives after biotransformation in the intestine conducted
by microorganism. Their antioxidant, anti-inflammatory and
cytoprotective activities are described extensively in literature and
are known since ancient times. Anti-inflammatory properties are of
special interest as adverse reactions in humans appear to be rare,
even with a daily exposure to flavonoids-containing food.

Several mechanisms are suggested for anti-inflammatory effects
of flavonoids. One of the most proved and complex mechanisms,
implicates an inhibition in the release of inflammatory molecules
such histamine, tryptase, IL-6, IL-8 and TNF-alfa, from activated
mast cells trough a phosphorylation of MACEDONIA (Mast Cell
Degranulation Inhibitor Agent) protein, involved in exocytosis (1).
The underlying mechanism of this action is based on an activation
of protein kinase C (PKC) calcium-independent and an inhibition of
other PKC enzymes and tyrosin-kinases that play a major role in the
inflammatory response.

Another mechanism proposed to justify the anti-inflammatory
activity, suggests an inhibition of enzymes of the cyclooxygenase
(COX) family, which produces the transformation of araquidonic
acid into proinflammatory prostaglandins, competitively (2) or
decreasing its transcription (3).

However, in a recent work, Nishizaki et al. (4) reported that
flavonoids are powerful agonist of glucocorticoid receptors.
Glucocorticoids bind the nuclear receptor, accelerating the
transcription of genes that codify for proteins like lipocortin-1 which
strongly inhibits the effect of phospholipase-2 that provides
araquidonic acid which is the substrate of COX. Thus, an indirect
anti-inflammatory effect can be expected by the interaction of
flavonoids with the glucocorticoid receptor (GR).

In the light of the diversity of plants with anti-inflammatory effect
mediated by flavonoids (5), it is of great value to develop a method
to predict the binding affinity to GR. For this reason the aim of this
work is to try to explain the binding mode of flavonoids and to
estimate the binding energy of the compounds based on experimental
values from gene expression assays and the linear interaction energy
(LIE) approximation (6).

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