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.
Badhan
Raj
R
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, UK.
Penny
Jeffrey
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004268:DNA-Binding Proteins; D005419:Flavonoids