Abstract
Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.
Highlights
Ovarian cancer (OC) ranks fifth leading cause of death among women and one of the deadliest cancers among all female genital malignancies [1–3]
Gemcitabine interacts with five amino acid residues (Asp951, Lys952, Glu1266, Glu1269, Thr1270) that lie in the loops of multidrug resistance protein 1 (MRP1) except one amino acid (Arg1066) residue which binds to TMD2
MRP1 was analyzed for docking against several anticancer drugs such as, Paclitaxel, Gemcitabine, Carboplatin, Doxorubicin, and Topotecan which are usually used to treat advanced stage ovarian cancer, to understand drug–target interactions
Summary
Ovarian cancer (OC) ranks fifth leading cause of death among women and one of the deadliest cancers among all female genital malignancies [1–3]. P-gp and MRP transporters recognize similar substrates apart from few anticancer drugs such as taxanes (Paclitaxel and Docetaxel) which are preferable substrates for P-gp Both P-gp and MRP have been reported to be involved in conferring multidrug resistance in OC [14]. Understanding the MRP1 substrates specificities would have a major impact in designing novel chemotherapeutic drugs in order to minimize MRP1-related drug–drug interactions In this present study, we aim to determine the binding site of MRP1 with various anticancer drugs using in silico analysis to determine the binding affinity and the potential interaction sites in full protein and to predict the best anticancer drugs that may be a promising choice to treat non-responder OC patients often caused due to overexpressed MRP1 transporter
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