The in silico identification of human bile salt export pump (ABCB11) inhibitors associated with cholestatic drug-induced liver injury

Drug-induced liver injury (DILI) is one of the major causes of drug attrition and failure. Currently, there is increasing evidence that direct inhibition of the human bile salt export pump (BSEP/ABCB11) by drugs and/or metabolites is one of the most important mechanisms of cholestatic DILI. In the present study, we employ two in silico methods, random forest (RF) and the pharmacophore method, to recognize potential BSEP inhibitors that could cause cholestatic DILI, with the aim of mitigating the risk of cholestatic DILI to some extent. The RF model achieved the best prediction performance, producing AUC (area under receiver operating characteristic curve) values of 0.901, 0.929 and 0.996 for leave-one-out cross-validation, the test set and the external test set, respectively, indicating that the built RF model has a satisfactory identification ability. As a complement to the RF model, the pharmacophore model was also built and was proved to be reliable with good predictive performance based on the internal and external validation results. Further analysis indicates that hydrophobicity, molecular size and polarity are important factors that influence the inhibitory activity of BSEP. Furthermore, the two models are applied to screen FDA-approved small molecule drugs, among which the drugs with the potential risk of cholestatic DILI are reported. In conclusion, the RF and pharmacophore models that we present can be considered as integrated screening tools to indicate the potential risk of cholestatic DILI by inhibition of BSEP.