Читать книгу Drug Transporters - Группа авторов - Страница 90

A variety of experimental approaches, including Bayesian machine learning, binary classification modeling, molecular docking and pharmacophore modeling, have been employed to define physicochemical and structural properties of MATE ligands. Inhibitors of MATE1 have been defined by their cationic charge, high molecular weight, and lipophilicity [53]. Using a combination of in vitro and computational approaches, a pharmacophore for hMATE1 and hMATE2‐K inhibitors was defined that favors shared features of high‐affinity inhibitors (such as pyrimethamine and quinidine) and avoids structures observed in low‐affinity inhibitors (such as histamine, caffeine, and chloramphenicol) [54]. Refinement of the model resulted in a pharmacophore for MATE inhibition that included two hydrophobes, a hydrogen‐bond acceptor, and an ionizable feature [54]. A subsequent combinatorial pharmacophore model for hMATE1 inhibition predicted multiple sites for ligand interaction. These included two regions for competitive inhibition by smaller molecules, as well as accommodation of large inhibitors within the central cavity of the transporter where they act noncompetitively to prevent the conformational changes needed for organic cation transport [55].

Transporter‐based drug–drug interactions can often be dependent upon the identity of the victim substrate being evaluated, as has been demonstrated for OCT [56, 57]. Interestingly, while some early studies with a small number of substrates suggested this may be the case for MATE transporters [58], a more robust subsequent analysis has suggested otherwise. Using four structurally distinct organic cation substrates (metformin, cimetidine, MPP, and N,N,N‐trimethyl‐2‐[methyl(7‐nitrobenzo[c][1,2,5]oxadiazol‐4‐yl)amino]ethanaminium iodide) and over 400 drugs, it was determined that the identity of the substrate has little influence on ligand interaction and inhibition of hMATE1‐mediated uptake of substrates in overexpressing cells [59]. Similar results were observed in a separate study using metformin and atenolol as substrates [60]. Notably, there were no significant differences in the apparent Michaelis constant of the transported substrate and the 50% inhibitor concentration calculated from the inhibition of transport across the four substrates. These data would suggest that there is a shared binding site for interaction of substrates and inhibitors on the external surface of hMATE1.