The values shown in italics represent measured apparent Kt values for the transport of the indicated substrate, rather than the ICfifty values.
The set of substrates used in the current study did not include the fluorescent OC, 4-(4-dimethylamino)styryl)-N-methylpyridinium (ASP), which has been used as a test substrate to assess selectivity of both ). In the study of MATE1 selectivity, Wittwer et al. (2013) screened 900+ compounds for inhibition of MATE1-mediated ASP transport and noted, as discussed subsequently in the present study, that cationic charge and hydrophobicity were positively correlated with inhibition of MATE1 activity. Eighty-six compounds in the set of ligands used in the current study were included in the Wittwer report and Supplemental Fig. 3A compares the degree of inhibition of MPP transport reported here with the inhibition of ASP transport reported in that study. There was a clear correlation between the inhibitions produced by this common set of ligands. Although it appeared that, in general, there was a greater degree of inhibition of MPP transport than of ASP transport (particularly evident for the higher affinity inhibitors distributed toward the left side in Supplemental Fig. 3A), this probably reflected the use of a 50 µM screening concentration in our study compared with a 20 µM screening concentration in the study by Wittwer et al. (2013). For five compounds, Supplemental Fig. 3B compares the IC50 values for inhibition of MPP or metformin transport that we determined to the values obtained by Wittwer et al. (2013) for inhibition of ASP transport. Within the limits of resolution provided by this small sample, there was little evidence for a systematic variation in IC50 values obtained for the two substrates.
Development of MATE1 Pharmacophores and you may Bayesian Host-Learning Designs.
Figure 9 shows the 3D pharmacophores developed from data on the inhibition produced by the 22 test drugs of the NCC plus the test substrates when used as inhibitors against MATE1-mediate transport of the four test substrates (total = 26 molecules). Each is shown overlaid with the structure of gabexate, which was a particularly good inhibitor of all four substrates. Given the relative independence of substrate identity on the profile of inhibition evident in Fig. 8, it was not unexpected that the four pharmacophores were generally quite similar to one another. Figure 10 shows the observed versus expected IC50 values calculated using these pharmacophores (MPP, r = 0.80; NBD-MTMA, r = 0.81; cimetidine, r = 0.81; metformin, r = 0.79). For MPP, NBD-MTMA, and cimetidine, each pharmacophore included two hydrogen bond acceptor features (green), one hydrophobic region (cyan), and an ionizable (i.e., cationic) feature (red). The pharmacophore developed for metformin (Fig. 9D) included only one hydrogen bond acceptor feature, two hydrophobic regions, and one ionizable feature; however, cluster analysis revealed little or no statistical difference between the pharmacophores, which is evident in the spatial alignment of the four pharmacophores (Fig. 9E).
The fresh pharmacophores were according to IC
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Common feature pharmacophores of MATE1 inhibitors. 50 values of 22 test drugs from the NCC plus the four test substrates when used as inhibitors of MATE-mediated transport of each labeled substrate [(A) MPP; (B) NBD-MTMA; (C) cimetidine; (D) metformin]. Each is shown overlaid with the structure of gabexate (IC50 values of 0.6–0.7 µM). Pharmacophore features are one ionizable (red; cationic) feature; one hydrophobe (cyan; two for metformin), and two hydrogen bond acceptors (green; one for metformin). (E) Spatial alignment of the four pharmacophores.
The latest pharmacophores have been considering IC
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50 values based on the models shown in Fig. 9. The dashed line represents identity between measured and predicted. Data points shown as circles represent the 26 compounds that comprised the training set for model development; the six points shown as green hexagons represent six test set compounds and their predicted versus measured values for inhibition of MPP transport (see Supplemental Table 1). For clarity, the individual regression lines (log measured versus log predicted) for the four substrates are not shown, but the r values for these lines are shown: MPP, 0.80; NBD-MTMA, 0.81; cimetidine, 0.81, and metformin, 0.79.
