title: A global drug inhibition pattern for the human ATP-binding cassette transporter breast cancer resistance protein (ABCG2).
abstract: In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity. An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.
authors.affiliation: Pharmaceutical Screening and Informatics, Department of Pharmacy, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden. Per.Artursson@farmaci.uu.se
authors.forename: Pär
authors.initials: P
authors.lastname: Matsson
authors.forename: Gunilla
authors.initials: G
authors.lastname: Englund
authors.forename: Gustav
authors.initials: G
authors.lastname: Ahlin
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001120:Arginine / Q000235:genetics / Q000502:physiology; D001667:Binding, Competitive; D001692:Biological Transport; D002460:Cell Line; D019295:Computational Biology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008942:Mitoxantrone / Q000493:pharmacokinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D001120:Arginine; D008942:Mitoxantrone