Structure-based ligand design of potential modulators of Multidrug Resistance Protein-1 (MRP-1)

Multidrug resistance (MDR) imposes a serious constraint on the successful chemotherapeutic treatment of cancer. ABC (ATP binding cassette) transporter activity is a highly significant factor 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, structural homology models of both N-terminal and C-terminal MRP-1 NBDs have been created. Control molecular docking studies of ATP were carried out to validate both model structure and the docking process. Docking of a series of flavonoid-based compounds known to interact at MRP-1 NBDs allowed investigation of the mechanisms by which compounds interact with the NBDs and definition of the structural characteristics required for high affinity binding. Mechanistic and structural information obtained in these studies will be employed to identify and design both existing and novel compounds capable of blocking transporter-mediated drug efflux. 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 and/or develop modulators capable of reversing MRP-1-mediated MDR, which may ultimately increase efficacy of chemotherapy-based cancer treatment.