The most common mechanism of the so-called multidrug resistance (MDR), is mainly associated with an over
expression of P-glycoprotein (Pgp). It is an ATP-dependent transport protein that limits the intracellular accumulation of a
variety of structurally unrelated compounds within various organs and normal tissues such as kidney, small intestine and
the blood brain barrier. Thus, the expression of Pgp has a major impact on the pharmacokinetic profile of many
therapeutic agents and therefore, overcoming Pgp-mediated efflux constitutes an attractive means of potentially enhancing
their therapeutic efficacy.
The flavonoids comprise a large group of polyphenolic compounds that occur in plants and vegetables, and they have
been shown to display a wide variety of biological activities. For example, anti-inflammatory, antioxidant, antiallergic,
hepatoprotective, antithrombotic, antiviral, and anticarcinogenic activities.
The interactions between flavonoids and Pgp have also been extensively studied and some quantitative structure-activity
relationships (QSAR) have been reported. In the present work, we have employed 2D-QSAR analysis to evaluate the
interactions between Pgp and several flavonoid compounds with the aim of identifying the molecular factors responsible
for the Pgp-binding affinity evidenced by these compounds. Thus, the reported data for dissociation constants (KD)
between Pgp and 62 flavonoid compounds were modeled by means of multiple regression analysis (MLR), and structures
of the compounds under study were characterized by means of calculated physicochemical properties and several
topological and constitutional descriptors, as well as geometrical and quantum chemical indexes. The obtained results
suggest that the hydrophobic and especially geometric factors are of prime importance for binding, whereas in the case of
flavonoid derivatives with flavone (flavonols), flavanone and isoflavone nuclei, the electronic factors are also involved in
electron donor/acceptor interactions. In addition, in the case of chalcones, the results suggest that the affinity toward P-gp
of such compounds is mainly governed by intermolecular dispersive interactions at the binding site.