title: Lack of Influence of Substrate on Ligand Interaction with the Human Multidrug and Toxin Extruder, MATE1.
abstract: Multidrug and toxin extruder (MATE) 1 plays a central role in mediating renal secretion of organic cations, a structurally diverse collection of compounds that includes ∼40% of prescribed drugs. Because inhibition of transport activity of other multidrug transporters, including the organic cation transporter (OCT) 2, 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 iodide. 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 three-dimensional 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.
authors.affiliation: Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona (L.J.M.-G., M.M., S.H.W.); and Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.).
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Martínez-Guerrero
authors.affiliation: Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona (L.J.M.-G., M.M., S.H.W.); and Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.).
authors.forename: Mark
authors.initials: M
authors.lastname: Morales
authors.affiliation: Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona (L.J.M.-G., M.M., S.H.W.); and Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.).
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona (L.J.M.-G., M.M., S.H.W.); and Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.) shwright@u.arizona.edu.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Wright
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D000069550:Machine Learning; D008958:Models, Molecular; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D008024:Ligands; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human