Computer-assisted drug design of potential modulators of Multidrug Resistance Protein-1 (MRP1)

Kanin Rungsardthong, Kanin Rungsardthong, Sergio Mares-Samano, Jeffrey Penny

Research output: Contribution to conferencePoster


Multidrug resistance (MDR) imposes a serious constraint on the successful chemotherapeutic treatment of cancer. ABC (ATP binding cassette) transporter activity is one of significant factors contributing to MDR. Overexpression of multidrug resistance-associated protein-1 (MRP-1) has been reported in a variety of solid tumours and haematological malignancies. The transporter can export hydrophobic and anionic anticancer agents, lead to decreased intracellular drug accumulation. Transport is dependent on functionally active nucleotide-binding domains (NBDs), which play a crucial role in ATP binding and hydrolysis, thereby energising drug export. Thus, inhibition of efflux transporter-mediated drug resistance by compounds capable of binding at the NBDs and disrupting the catalytic cycle may be a promising approach to overcome MRP-1-mediated MDR. In an attempt to design NBD targeted transporter modulators, we here showed the implementation of high-throughput virtual screening that led to identifying promising compounds to be active in the large commercially available database. The approach included the pharmacophore generation of query structures; virtual screening based on pharmacophore model, structure-based molecular docking and generation of structural homology models of both N-terminal and C-terminal MRP-1 NBDs. The Zinc database of commercially available compounds containing approximately 13 million compounds was employed as library targets for screening. Pharmacophore perception has been generated through chemical and topological feature for MRP-1 modulatory effect of flavonoid-based structure. These features were subsequently used as a fingerprint for screening through the Zinc database. The hits were virtually docked into both NBDs. The ultimate compounds will be selected through the docking orientation and affinity. Future work will determine the abilities of compounds predicted to bind to the NBDs with high affinity to reverse MRP-1-mediated multidrug resistance in vitro using MRP-1 transfected cell lines. This research could help identify modulators capable of reversing MRP-1-mediated MDR, which may ultimately enhance efficacy of chemotherapy-based cancer treatment.
Original languageEnglish
Publication statusPublished - Jul 2010
Event5th Joint Sheffield Conference on Chemoinformatics - The Octagon Centre, University of Sheffield
Duration: 13 Jul 201015 Jul 2010


Conference5th Joint Sheffield Conference on Chemoinformatics
CityThe Octagon Centre, University of Sheffield


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