Toward predicting drug-induced liver injury: parallel computational approaches to identify multidrug resistance protein 4 and bile salt export pump inhibitors.
Drug-induced liver injury (DILI) is an important cause of drug toxicity. Inhibition of multidrug resistance protein 4 (MRP4), in addition to bile salt export pump (BSEP), might be a risk factor for the development of cholestatic DILI. Recently, we demonstrated that inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. Here, we aimed to develop computational models to delineate molecular features underlying MRP4 and BSEP inhibition. Models were developed using 257 BSEP and 86 MRP4 inhibitors and noninhibitors in the training set. Models were externally validated and used to predict the affinity of compounds toward BSEP and MRP4 in the DrugBank database. Compounds with a score above the median fingerprint threshold were considered to have significant inhibitory effects on MRP4 and BSEP. Common feature pharmacophore models were developed for MRP4 and BSEP with LigandScout software using a training set of nine well characterized MRP4 inhibitors and nine potent BSEP inhibitors. Bayesian models for BSEP and MRP4 inhibition/noninhibition were developed with cross-validated receiver operator curve values greater than 0.8 for the test sets, indicating robust models with acceptable false positive and false negative prediction rates. Both MRP4 and BSEP inhibitor pharmacophore models were characterized by hydrophobic and hydrogen-bond acceptor features, albeit in distinct spatial arrangements. Similar molecular features between MRP4 and BSEP inhibitors may partially explain why various drugs have affinity for both transporters. The Bayesian (BSEP, MRP4) and pharmacophore (MRP4, BSEP) models demonstrated significant classification accuracy and predictability.
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (M.A.W., P.W.S.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.K., T.J.U., K.L.R.B.); Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina (T.J.U.).
Matthew A
MA
Welch
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (M.A.W., P.W.S.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.K., T.J.U., K.L.R.B.); Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina (T.J.U.).
Kathleen
K
Köck
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (M.A.W., P.W.S.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.K., T.J.U., K.L.R.B.); Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina (T.J.U.).
Thomas J
TJ
Urban
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (M.A.W., P.W.S.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.K., T.J.U., K.L.R.B.); Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina (T.J.U.).
Kim L R
KL
Brouwer
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (M.A.W., P.W.S.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.K., T.J.U., K.L.R.B.); Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina (T.J.U.) pswaan@rx.umaryland.edu.
Peter W
PW
Swaan
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D001499:Bayes Theorem; D001647:Bile Acids and Salts / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002779:Cholestasis / Q000378:metabolism; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D012307:Risk Factors
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C093491:ABCB11 protein, human; C073492:ABCC4 protein, human