RT Journal Article
SR Electronic
T1 Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 743
OP 755
DO 10.1124/jpet.112.191577
VO 341
IS 3
A1 Astorga, Bethzaida
A1 Ekins, Sean
A1 Morales, Mark
A1 Wright, Stephen H.
YR 2012
UL http://jpet.aspetjournals.org/content/341/3/743.abstract
AB The present study compared the selectivity of two homologous transport proteins, multidrug and toxin extruders 1 and 2-K (MATE1 and MATE2-K), and developed three-dimensional pharmacophores for inhibitory ligand interaction with human MATE1 (hMATE1). The human orthologs of MATE1 and MATE2-K were stably expressed in Chinese hamster ovary cells, and transport function was determined by measuring uptake of the prototypic organic cation (OC) substrate 1-methyl-4-phenylpyridinium (MPP). Both MATEs had similar apparent affinities for MPP, with Ktapp values of 4.4 and 3.7 μM for MATE1 and MATE2-K, respectively. Selectivity was assessed for both transporters from IC50 values for 59 structurally diverse compounds. Whereas the two transporters discriminated markedly between a few of the test compounds, the IC50 values for MATE1 and MATE2-K were within a factor of 3 for most of them. For hMATE1 there was little or no correlation between IC50 values and the individual molecular descriptors LogP, total polar surface area, or pKa. The IC50 values were used to generate a common-features pharmacophore, quantitative pharmacophores for hMATE1, and a Bayesian model suggesting molecular features favoring and not favoring the interaction of ligands with hMATE1. The models identified hydrophobic regions, hydrogen bond donor and hydrogen bond acceptor sites, and an ionizable (cationic) feature as key determinants for ligand binding to MATE1. In summary, using a combined in vitro and computational approach, MATE1 and MATE2-K were found to have markedly overlapping selectivities for a broad range of cationic compounds, including representatives from seven novel drug classes of Food and Drug Administration-approved drugs.