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.

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

“…In agreement, substrate-dependent inhibition (MPP + versus metformin) of OCT2 has been observed. For example, Zolk et al (2009) More recently, substrate-dependent inhibition has also been reported for MATE1 (Martinez-Guerrero and Wright, 2013).…”

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

“…Stock solutions of PF-04971729 were prepared in dimethyl sulfoxide (DMSO). The hOCT2 inhibitor quinidine (1 mM) was used as a positive control (Zolk et al, 2009). Incubations were performed in 24-well culture plates using […”

Functional Characterization of the Human Organic Cation Transporter 2 Variant p.270Ala>Ser

“…Transport assays were performed as described previously (Solbach et al, 2008;Zolk et al, 2009 (Zolk et al, 2009). These potential inhibitors were selected based on previous publications suggesting them as substrates/inhibitors of OCT2 and/or on the presence of physicochemical characteristics generally associated with OCT2 substrates/ inhibitors, such as net positive charge at the amine nitrogen at physiological pH and molecular weight Ͻ500.…”