In silico modelling of the interaction of flavonoids with human P-glycoprotein nucleotide-binding domain

A three-dimensional model of human ABCB1 nucleotide-binding domain (NBD) was developed by homology modelling using the high-resolution human TAP1 transporter structure as template. Interactions between NBD and flavonoids were investigated using in silico docking studies. Ring-A of unmodified flavonoid was located within the NBD P-loop with the 5-hydroxyl group involved in hydrogen bonding with Lys1076. Ring-B was stabilised by hydrophobic stacking interactions with Tyr1044. The 3-hydroxyl group and carbonyl oxygen were extensively involved in hydrogen bonding interactions with amino acids within the NBD. Addition of prenyl, benzyl or geranyl moieties to ring-A (position-6) and hydrocarbon substituents (O-n-butyl to O-n-decyl) to ring-B (position-4) resulted in a size-dependent decrease in predicted docking energy which reflected the increased binding affinities reported in vitro.