Human MRP1 protein plays a vital role in cancer multidrug resistance. Coumarins show promising pharmacological properties. Virtual screening, ADMET, molecular docking and molecular dynamics (MD) simulations were utilized as pharmacoinformatic tools to identify potential MRP1 inhibitors among coumarin derivatives. Using in silico ADMET, 50 hits were further investigated for their selectivity toward the nucleotide-binding domains (NBDs) of MRP1 using molecular docking. Accordingly, coumarin, its symmetrical ketone derivative Lig. No. 4, and Reversan were candidates for focused docking study with the NBDs domains compared with ATP. The result indicates that Lig. No. 4, with the best binding score, interacts with NBDs via hydrogen bonds with residues: GLN713, LYS684, GLY683, CYS682 in NBD1, and GLY1432, GLY771, SER769 and GLN1374 in NBD2, which mostly overlap with ATP binding residues. Moreover, doxorubicin (Doxo) was docked to the transmembrane domains (TMDs) active site of MRP1. Doxo interaction with TMDs was subjected to MD simulation in the NBDs free and occupied with Lig. No. 4 states. The results showed that Doxo interacts more strongly with TMD residues in inward facing feature of TMDs helices. However, when Lig. No. 4 exists in NBDs, Doxo interactions are different, and TMD helices show more outward-facing conformation. This result may suggest a partial competitive inhibition mechanism for the Lig. No. 4 on MRP1 compared with ATP. So, it may inhibit active complex formation by interfering with ATP entrance to NBDs and locking MRP1 conformation in outward-facing mode. This study suggests a valuable coumarin derivative that can be further investigated for potent MRP1 inhibitors.Communicated by Ramaswamy H. Sarma.
Keywords: ABC transporter membrane proteins; MRP1; Multidrug resistance; cancer; coumarin derivatives; molecular docking; molecular dynamics.
HIGHLIGHTSVirtual screening scored a symmetrical ketone derivative IUPAC ([2-[(1E, 4E)-5-(2-acetyloxyphenyl)-3-oxopenta-1, 4-dienyl] phenyl] acetate); PubChem CID 5468558 (Lig. No. 4 in this study) as the best candidate among coumarins to inhibit MRP1.This compound binds to NBD1 and NBD2 of ABC transporters via hydrogen bonds shared with residues that are also involved in the ATP binding.This result, if not at all, suggest a partial competitive inhibition mechanism for Lig. No. 4 on the MRP1 protein.Molecular dynamics simulation study reveals different doxorubicin binding modes in interaction with MRP1 transmembrane domain in free and occupied NBDs with Lig. No. 4.Lig. No. 4 is a valuable candidate for further drug development studies to suppress drug resistance.