PT  - JOURNAL ARTICLE
AU  - Bethzaida Astorga
AU  - Sean Ekins
AU  - Mark Morales
AU  - Stephen H. Wright
TI  - Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K
AID  - 10.1124/jpet.112.191577
DP  - 2012 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 743--755
VI  - 341
IP  - 3
4099  - http://jpet.aspetjournals.org/content/341/3/743.short
4100  - http://jpet.aspetjournals.org/content/341/3/743.full
SO  - J Pharmacol Exp Ther2012 Jun 01; 341
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.