In silico design of potential modulators of ABCB1 and ABCG2 transport activity

Molecular modelling techniques were implemented to identify potential modulators of ABCB1 and ABCG2 targeted to the nucleotide-binding domains (NBDs) and to predict, at the molecular level, putative mechanisms of ligand-transporter interaction. Three-dimensional models of the NBDs of ABCB1 and ABCG2 were constructed by homology modelling. Stereochemical robustness and functional validity of models were demonstrated by accurately correlating the docking characteristics of a series of flavonoids and steroids with the findings of reported in vitro functional studies. Homology models were subsequently used to identify potential modulators targeted to the NBDs of ABCB1 and ABCG2 by virtual screening of the diversity set II database of the National Cancer Institute. Based on predicted affinity and binding orientation within the ATP-binding pocket of NBDs, compounds possessing predicted high binding affinity were successfully identified. Homology models of the NBDs of ABCB1 and ABCG2 were also employed for de novo design of potential modulators. Based on the three-dimensional structures of NBDs, and using flavonoid-frames as 'seed structures', a chemically unique set of molecules with a predicted high affinity to the ATP-binding pockets of both transporters, was constructed. In addition to homology models of the NBDs, a stereochemically robust three-dimensional atomic model of human ABCB1 was constructed by homology modelling using the recently elucidated high-resolution structure of mouse ABCB1 as template. Interactions between human ABCB1 and a number of substrates and inhibitors were investigated employing in silico docking studies. Predicted docking conformations of substrates/inhibitors within human ABCB1 suggest the existence of multiple binding sites located mainly in the vicinity of the internal cavity.EThOS - Electronic Theses Online ServiceGBUnited Kingdo