Potent inhibitors of human organic anion transporters 1 and 3 from clinical drug libraries: discovery and molecular characterization - PubMed (original) (raw)

. 2012 Nov 5;9(11):3340-6.

doi: 10.1021/mp300365t. Epub 2012 Sep 25.

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Potent inhibitors of human organic anion transporters 1 and 3 from clinical drug libraries: discovery and molecular characterization

Peng Duan et al. Mol Pharm. 2012.

Abstract

Transporter-mediated drug-drug interactions in the kidney dramatically influence the pharmacokinetics and other clinical effects of drugs. Human organic anion transporters 1 (hOAT1) and 3 (hOAT3) are the major transporters in the basolateral membrane of kidney proximal tubules, mediating the rate-limiting step in the elimination of a broad spectrum of drugs. In the present study, we screened two clinical drug libraries against hOAT1 and hOAT3. Of the 727 compounds screened, 92 compounds inhibited hOAT1 and 262 compounds inhibited hOAT3. When prioritized based on the peak unbound plasma concentrations of these compounds, three inhibitors for hOAT1 and seven inhibitors for hOAT3 were subsequently identified with high inhibitory potency (>95%). Computational analyses revealed that inhibitors and noninhibitors can be differentiated from each other on the basis of several physicochemical features, including number of hydrogen-bond donors, number of rotatable bonds, and topological polar surface area (TPSA) for hOAT1; and molecular weight, number of hydrogen-bond donors and acceptors, TPSA, partition coefficient (log P(7.4)), and polarizability for hOAT3. Pharmacophore modeling identified two common structural features associated with inhibitors for hOAT1 and hOAT3, viz., an anionic hydrogen-bond acceptor atom, and an aromatic center separated by ∼5.7 Å. Such model provides mechanistic insights for predicting new OAT inhibitors.

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Figures

Fig. 1

Fig. 1. Concentration dependence of 6-CF uptake in hOAT1- and hOAT3- expressing cells

a. The hOAT1-mediated specific uptake was calculated by subtracting the nonspecific uptake in control cells from that in the cells expressing hOAT1. b. The hOAT3-mediated specific uptake was calculated by subtracting the nonspecific uptake in control cells from that in the cells expressing hOAT3.

Fig. 2

Fig. 2. Inhibitors of hOAT1 and hOAT3 identified in a screen of 727 clinically tested drugs

a. Overview of the results from the screening of hOAT1 inhibition. The 92 compounds (at 50μM) resulting in at least 50% decreased uptake of 6-CF were classified as inhibitors (shaded in light gray and under the curve). Data were presented as the mean ± SD (samples in triplicate from one experiment). b. Overview of the results from the screening of hOAT3 inhibition. The 262 compounds (at 20μM) resulting in at least 50% decreased uptake of 6-CF were classified as inhibitors (shaded in light gray and under the curve). Data were presented as the mean ± SD (samples in triplicate from one experiment).

Fig. 3

Fig. 3. Structural features of hOAT1 and hOAT3 inhibitors

a. Distribution of key physicochemical properties of hOAT1 inhibitors. b. Distribution of key physicochemical properties of hOAT3 inhibitors. The calculated descriptors (viz., TPSA, molecular weight, volume, number of rotatable bonds, Log P7.4, molecular polarizability, number of hydrogen-bond donors and hydrogen-bond acceptors) were calculated using Chemaxon JChem package (ChemAxon, USA). The frequency distribution analysis was conducted between inhibitors and non-inhibitors by Graphpad prism 5.0. *P < 0.05 was considered significantly different, and n.s. stood for no significant difference.

Fig. 3

Fig. 3. Structural features of hOAT1 and hOAT3 inhibitors

a. Distribution of key physicochemical properties of hOAT1 inhibitors. b. Distribution of key physicochemical properties of hOAT3 inhibitors. The calculated descriptors (viz., TPSA, molecular weight, volume, number of rotatable bonds, Log P7.4, molecular polarizability, number of hydrogen-bond donors and hydrogen-bond acceptors) were calculated using Chemaxon JChem package (ChemAxon, USA). The frequency distribution analysis was conducted between inhibitors and non-inhibitors by Graphpad prism 5.0. *P < 0.05 was considered significantly different, and n.s. stood for no significant difference.

Fig. 4

Fig. 4

Structures of inhibitors used in pharmacophore analysis.

Fig. 5

Fig. 5. Pharmacophore model of hOAT1 and hOAT3 inhibitors

Two representative OAT inhibitors were mapped to the proposed pharmacophore model. The anionic and hydrogen-bond acceptor atom is displayed as cyan sphere and labeled F1:Ani &Acc, while the aromatic center is represented as a yellow sphere and labeled F2:Aro. Carbon atoms in the compound (CID: 84003) is colored in magenta and those in the compound (CID: 60560) is shown in gray. The other atoms in the compounds are colored by atom type (nitrogen: blue; oxygen: red; sulfur: yellow).

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