RT Journal Article
SR Electronic
T1 Lack of Influence of Substrate on Ligand Interaction with Human MATE1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.105056
DO 10.1124/mol.116.105056
A1 Lucy J Martinez-Guerrero
A1 Mark H Morales
A1 Sean Ekins
A1 Stephen H Wright
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/07/14/mol.116.105056.abstract
AB Multidrug And Toxin Extruder 1 (MATE1) plays a central role in mediating renal secretion of organic cations, a structurally diverse collection of compounds that includes ~40% of prescribed drugs. Because ligand inhibition of transport activity of other multidrug transporters, including the organic cation transporter OCT2, is influenced by the structure of the transported substrate, the present study screened over 400 drugs as inhibitors of the MATE1-mediated transport of four structurally distinct organic cation substrates: the commonly used drugs (1) metformin and (2) cimetidine; and two prototypic cationic substrates, (3) 1-methyl-4-phenylpyridinium (MPP) and, (4) the novel fluorescent probe, N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA). Transport was measured in Chinese hamster ovary cells that stably expressed the human ortholog of MATE1. Comparison of the resulting inhibition profiles revealed no systematic influence of substrate structure on inhibitory efficacy. Similarly, IC50 values for 26 structurally diverse compounds revealed no significant influence of substrate structure on the kinetic interaction of inhibitor with MATE1. The IC50 data were used to generate 3D quantitative pharmacophores that identified hydrophobic regions, H-bond acceptor sites, and an ionizable (cationic) feature as key determinants for ligand binding to MATE1. In summary, in contrast to the behavior observed with some other multidrug transporters, including OCT2, the results suggest that substrate identity exerts comparatively little influence on ligand interaction with MATE1.