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Identification of Novel BCRP Inhibitors by Virtual Screening.


Mol Pharm. 2013 Feb 18;


Authors: Pan Y, Chothe PP, Swaan PW


Abstract

Breast Cancer Resistance Protein (BCRP; ABCG2) is an efflux transporter that plays an important role in multi-drug 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 and were validated with external test sets. 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 [3H]-mitoxantrone in MCF-7/AdrVp cells. Nineteen new drugs were identified with significantly 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.

PMID: 23418667 [PubMed - as supplied by publisher]