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[摘要]：The chem. space of registered oral drugs was explored for inhibitors of the human multidrug-resistance assocd. protein 2 (MRP2; ABCC2), using a data set of 191 structurally diverse drugs and drug-like compds. The data set included a new ref. set of 75 compds., for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compds. assocd. with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17b-D-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addn., 13 compds. were shown to stimulate the transport of estradiol-17b-D-glucuronide. The exptl. results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their mol. structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity. |
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