An in-silico investigation of protein–ligand interactions involving dietary flavonoids targeting the nucleotide-binding domain 1 (NBD1) of multidrug resistance-associated protein 1 (MRP1) to overcome multidrug resistance in cancer

Abstract

Multidrug resistance (MDR) continues to pose a tough challenge in the successful chemotherapeutic management of various malignancies. A key contributor to MDR is the multidrug resistance-associated protein 1 (MRP1), a member of the ATP-binding cassette (ABC) transporter family comprising 1531 amino acids. MRP1 actively extrudes a broad spectrum of chemotherapeutic agents from cancer cells, thereby reducing their intracellular accumulation and attenuating their cytotoxic effects. In this study, we performed molecular docking analyses to investigate the binding interactions between a series of naturally occurring dietary flavonoids and the Nucleotide Binding Domain 1 (NBD1) of MRP1, aiming to identify structural determinants that enhance ligand affinity and inform the selection of effective MDR modulators. All docking simulations were conducted using the Glide v5.7 software suite (Schrödinger LLC., Portland, USA) in extra precision mode (GlideXP). The 14 naturally occuring flavonoids assessed, rutin, taxifolin, myricetin, isorhamnetin, apigenin, eriodictyol, chrysin, daidzein and genistein exhibited variable binding affinities toward MRP1-NBD1, with several compounds forming key hydrogen bonds with active site amino acid residues. Notably, rutin demonstrated the highest binding affinity (docking score: –10.1958), forming highly stable hydrogen bonds with SER686 and SER689. Taxifolin and myricetin also showed favorable interactions, primarily involving SER686. These findings highlight the potential of specific dietary flavonoids to serve as functional inhibitors of MRP1-mediated drug efflux. Overall, the structural insights gained underscore the utility of flavonoid based scaffolds as promising candidates for overcoming MDR, thereby improving the therapeutic efficacy of anticancer agents.