Simultaneous Prediction of four ATP‐binding Cassette Transporters’ Substrates Using Multi‐label QSAR

Efflux by the ATP-binding cassette (ABC) transporters affects the pharmacokinetic profile of drugs and it has been implicated in drug-drug interactions as well as its major role in multi-drug resistance in cancer. It is therefore important for the pharmaceutical industry to be able to understand what phenomena rule ABC substrate recognition. Considering a high degree of substrate overlap between various members of ABC transporter family, it is advantageous to employ a multi-label classification approach where predictions made for one transporter can be used for modeling of the other ABC transporters. Here, we present decision tree-based QSAR classification models able to simultaneously predict substrates and non-substrates for BCRP1, P-gp/MDR1 and MRP1 and MRP2, using a dataset of 1493 compounds. To this end, two multi-label classification QSAR modelling approaches were adopted: Binary Relevance (BR) and Classifier Chain (CC). Even though both multi-label models yielded similar predictive performances in terms of overall accuracies (close to 70 %), the CC model overcame the problem of skewed performance towards identifying substrates compared with non-substrates, which is a common problem in the literature. The models were thoroughly validated by using external testing, applicability domain and activity cliffs characterization. In conclusion, a multi-label classification approach is an appropriate alternative for the prediction of ABC efflux.