Abstract
Multidrug resistance (MDR) is the major cause, by which cancer cells expel the drugs out, developing a challenge against the current chemotherapeutic drugs regime. This mechanism is attributed to the over expression of ABC transporters like MRP1 on the surface of cells. Since nucleotide binding domains (NBD) of ABC transporters are the site of ATP binding and hydrolysis, thereby in this study we have targeted NBD1 of MRP1using molecular docking and molecular dynamic simulations (MDS). The compounds present in the FDA approved library were docked against NBD1 of the human multidrug resistance associated protein 1 (PDB ID: 2CBZ). For the docking studies, Standard Precision and Extra Precision methods were employed. After the EP docking studies, ligands showed an extremely low docking score that was indicative of very high binding affinity of the ligands to the NBD. Apart from the low docking score, another short listing criterion in simulation studies was the interaction of incoming ligand with the desired conserved residues of NDB involved in ATP binding and hydrolysis. Based on these measures, potassium citrate (DB09125) and technetium Tc-99m medronate (DB09138) were chosen and subjected to 100 ns simulation studies. From the MDS study we concluded that between these two compounds, potassium citrate is a better candidate for targeting MRP1.
Highlights
MRP1, a 190 kDa protein is capable of exporting hydrophobic drug molecules, folates, glutathione conjugated compounds, glucornoid conjugated steroids and organic anions to name a few[6]
As per the information about the active site and the residues of the nucleotide binding domains (NBD) involved in ATP hydrolysis, it is rational to look for the interaction of these target residues with the ligand
Among the four compounds we identified that Potassium citrate (DB09125) has the highest binding affinity of −16.765 Kcal.mol−1 toward ATP binding site of NBD domain
Summary
MRP1, a 190 kDa protein is capable of exporting hydrophobic drug molecules, folates, glutathione conjugated compounds, glucornoid conjugated steroids and organic anions to name a few[6]. It is a 1531 amino acid protein with two Nucleotide Binding Domains (NBD) and three Membrane Spanning Domains (MSDs) namely MSD0, www.nature.com/scientificreports/. One feature common to all ABC family members is the dependence of their ATPase activity on the cooperative interactions between the two NBDs. It has already been proved that both of the NBDs are involved in the transport of substrates across the cell and the binding and release of substrate depends on the ordered binding of ATP to the two NBDs. In addition to this, ATP binding is essential for the export of substrates converting the protein from a high-affinity to low affinity substrate binding state[9,10]. The inhibitory effect of curcumin on MRP1 has been studied by in silico studies
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