title: The in silico identification of human bile salt export pump (ABCB11) inhibitors associated with cholestatic drug-induced liver injury.
abstract: 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.
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, China.
authors.forename: Lili
authors.identifier: http://orcid.org/0000-0001-5664-5850
authors.initials: L
authors.lastname: Xi
authors.affiliation: Department of Science and Technology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, China.
authors.forename: Xin'an
authors.initials: X
authors.lastname: Wu
authors.affiliation: College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China. lishuyan@lzu.edu.cn.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China. lishuyan@lzu.edu.cn.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Li
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000737:chemistry*; D001647:Bile Acids and Salts / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D012372:ROC Curve; D015203:Reproducibility of Results; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D054852:Small Molecule Libraries