Abstract:Overexpression of ABC transporters leads to MDR (Multiple Drug Resistance). MDR is considered to be the major contributor to failure of chemotherapy in metastatic cancers. ABC transporters have protective role in normal cells by extruding xenobiotics of cytotoxic compounds from the cell. The development of selective inhibitors of P-gp, MRP1, MRP2, and BCRP has been a major goal of many research groups in the last few years. Previous studies have shown that 1,4-dihydropyridines could inhibit these transporters. In this study, some new 1,4-dihydropyridine and pyrimidine have been developed and their inhibitory effect on the resistant cancer cell lines was examined. In order to elucidate the binding mode of these compounds, a molecular docking and molecular dynamic simulation was performed for the protein-ligand complex. Dihydropyridines were more potent than dihydropyrimidines. However, one of the dihydropyrimidine derivatives selectively inhibited BCRP. The binding mode of these compounds showed that methoxy groups and heterocyclic rings could create hydrogen bonds with polar residues at the active sites. These regions were more stable during MD simulation.