Targeting MRP1 for the reversal of Multi-drug Resistance in cancer

Traditional chemotherapy treatment consists of various types of anti-cancer agents. The success of the treatment depends on reaching effective drug concentration inside the cancerous cells. Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette (ABC) exporter that normally protects tissues from toxic molecules. However, over-expression of MRP1 has been shown to confer Multidrug Resistance (MDR), phenomenon in which cancer cells are capable to defend themselves against broad variety of drugs. MRP1 extrudes many chemotherapeutic agents out of the tumor cells, thus reduces their accumulation. The tumors achieve high drug tolerance and survival rates, and the efficiency of treatment is severely harmed. Despite a broad range of studies regarding MRP1, including a relatively new Cryo-EM structure, the accurate mechanism remains vague. It is not clear yet how exactly the protein is able to extrude with exceptional diversity of ligands, both endogenous and exogenous. Many efforts have been made towards the discovery of modulators that inhibit its MDR activity. In this study, we suggest the existence of another unknown binding site that is responsible for the translocation of several widely used anti-cancer drugs. We analyzed different conformations of the protein, mutated it, and separately docked different ligands and a suggested modulator. For this purpose, we used several computational techniques such as homology modeling, various docking algorithms, Molecular Dynamics simulations, and normal mode analyses. Our findings run parallel with the experimental data from our collaborators and are essential for the future design of MRP1 modulators that will tremendously improve the success of treatment.