Virtual screening of ABCC1 transporter nucleotidebinding domains as a therapeutic target in multidrug resistant cancer

ABCC1 is a member of the ATP-binding Cassette super family of transporters, actively effluxes xenobiotics from cells. Clinically,ABCC1 expression is linked to cancer multidrug resistance. Substrate efflux is energised by ATP binding and hydrolysis at thenucleotide-binding domains (NBDs) and inhibition of these events may help combat drug resistance. The aim of this study is toidentify potential inhibitors of ABCC1 through virtual screening of National Cancer Institute (NCI) compounds. A threedimensionalmodel of ABCC1 NBD2 was generated using MODELLER whilst the X-ray crystal structure of ABCC1 NBD1 wasretrieved from the Protein Data Bank. A pharmacophore hypothesis was generated based on flavonoids known to bind at theNBDs using PHASE, and used to screen the NCI database. GLIDE was employed in molecular docking studies for all hitcompounds identified by pharmacophore screening. The best potential inhibitors were identified as compounds possessingpredicted binding affinities greater than ATP. Approximately 5% (13/265) of the hit compounds possessed lower docking scoresthan ATP in ABCC1 NBD1 (NSC93033, NSC662377, NSC319661, NSC333748, NSC683893, NSC226639, NSC94231, NSC55979,NSC169121, NSC166574, NSC73380, NSC127738, NSC115534), whereas approximately 7% (7/104) of docked NCI compounds werepredicted to possess lower docking scores than ATP in ABCC1 NBD2 (NSC91789, NSC529483, NSC211168, NSC318214,NSC116519, NSC372332, NSC526974). Analyses of docking orientations revealed P-loop residues of each NBD and the aromaticamino acids Trp653 (NBD1) and Tyr1302 (NBD2) were key in interacting with high-affinity compounds. On the basis of dockedorientation and docking score the compounds identified may be potential inhibitors of ABCC1 and require further pharmacologicalanalysis.

Abbreviations

ABC - ATP-binding cassette, DHS - dehydrosilybin, MDR - multidrug resistance, NBD - nucleotide-binding domain, PDB - protein data bank.