title: Identification of novel breast cancer resistance protein (BCRP) inhibitors by virtual screening.
abstract: Breast cancer resistance protein (BCRP; ABCG2) is an efflux transporter that plays an important role in multidrug resistance to antineoplastic drugs. The identification of drugs as BCRP inhibitors could aid in designing better therapeutic strategies for cancer treatment and will be critical for identifying potential drug-drug interactions. In the present study, we applied ligand-based virtual screening combined with experimental testing for the identification of novel drugs that can possibly interact with BCRP. Bayesian and pharmacophore models generated with known BCRP inhibitors were validated with an external test set. The resulting models were applied to predict new potential drug candidates from a database with more than 2000 FDA-approved drugs. Thirty-three drugs were tested in vitro for their inhibitory effects on BCRP-mediated transport of [(3)H]-mitoxantrone in MCF-7/AdrVp cells. Nineteen drugs were identified with significant inhibitory effect on BCRP transport function. The combined strategy of computational and experimental approaches in this paper has suggested potential drug candidates and thus represents an effective tool for rational identification of modulators of other proteins.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
authors: Yongmei
authors: Y
authors: Pan
authors: Paresh P
authors: PP
authors: Chothe
authors: Peter W
authors: PW
authors: Swaan
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001499:Bayes Theorem; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015203:Reproducibility of Results; 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; D008024:Ligands; D009363:Neoplasm Proteins