title: Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2).
abstract: The organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney, which is the essential step in their elimination from the organism. Although many drugs have been identified which interact with human OCT2, structural elements required for an interaction with OCT2 are not well defined. To address this issue, HEK293 cells stably expressing human OCT2 were generated. IC(50) values of commonly used drugs for inhibition of [(3)H]MPP(+) uptake were determined and correlated with physicochemical descriptors. We found only a significant correlation between the topological polar surface area (TPSA) and IC(50) values (r = 0.71, p < 0.0001). Structural alignment of most potent inhibitor drugs of OCT2-mediated MPP(+) uptake was used to construct a two-point pharmacophore consisting of an ion-pair interaction site and a hydrophobic aromatic site separated by 5.0 A. Taken together, our data identify structural determinants for inhibitor interactions with OCT2.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstr. 17, 91054, Erlangen, Germany. zolk@pharmakologie.uni-erlangen.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Solbach
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008687:Metformin / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008970:Molecular Weight; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014162:Transfection
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations; C491013:SLC22A2 protein, human; D012997:Solvents; D008687:Metformin; D015655:1-Methyl-4-phenylpyridinium