title: Virtual Screening of DrugBank Reveals Two Drugs as New BCRP Inhibitors.
abstract: The breast cancer resistance protein (BCRP) is an ABC transporter playing a crucial role in the pharmacokinetics of drugs. The early identification of substrates and inhibitors of this efflux transporter can help to prevent or foresee drug-drug interactions. In this work, we built a ligand-based in silico classification model to predict the inhibitory potential of drugs toward BCRP. The model was applied as a virtual screening technique to identify potential inhibitors among the small-molecules subset of DrugBank. Ten compounds were selected and tested for their capacity to inhibit mitoxantrone efflux in BCRP-expressing PLB985 cells. Results identified cisapride (IC50= 0.4 µM) and roflumilast (IC50= 0.9 µM) as two new BCRP inhibitors. The in silico strategy proved useful to prefilter potential drug-drug interaction perpetrators among a database of small molecules and can reduce the amount of compounds to test.
authors.affiliation: 1 University of Vienna, Department of Pharmaceutical Chemistry, Vienna, Austria.
authors.forename: Floriane
authors.initials: F
authors.lastname: Montanari
authors.affiliation: 1 University of Vienna, Department of Pharmaceutical Chemistry, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Cseke
authors.affiliation: 1 University of Vienna, Department of Pharmaceutical Chemistry, Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wlcek
authors.affiliation: 1 University of Vienna, Department of Pharmaceutical Chemistry, Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D020117:Cisapride / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D016015:Logistic Models; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011336:Probability; D012372:ROC Curve; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000631:Aminopyridines; D000970:Antineoplastic Agents; D001549:Benzamides; D003521:Cyclopropanes; D009363:Neoplasm Proteins; C424423:Roflumilast; D020117:Cisapride
keywords: BCRP inhibition; cisapride; logistic regression; roflumilast; virtual screening