title: Integrating Drug's Mode of Action into Quantitative Structure-Activity Relationships for Improved Prediction of Drug-Induced Liver Injury.
abstract: Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type, while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating the drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a data set of 333 drugs. The drugs were first grouped according to their MOA profiles (positive or negative in each MOA) based on the Tox21 qHTS assays. QSAR models for individual MOA assays were developed and subsequently combined to obtain the MOA-DILI model. A hold-out testing strategy (222 drugs for training and 111 drugs as a test set) was employed, which yielded a predictive accuracy of 0.711. The MOA-DILI model was directly compared with the standard QSAR approach using the same hold-out strategy, and the QSAR model yielded an accuracy of 0.662. To minimize the random chance in splitting training/test sets, the hold-out testing process was repeated 1000 times, and the observed difference in prediction accuracy between MOA-DILI and QSARs was statistically significant (P value <0.0001). Out of 17 MOAs used, four assays (i.e., antioxidant response elements, PPAR-gamma, estrogen receptor, and thyroid receptor assays) contributed most to the improved prediction of the MOA-DILI model over QSARs. In conclusion, the MOA-DILI approach has the potential to significantly improve predictive outcomes and to reveal complex relationships between MOAs and DILI, all of which would be helpful in developing DILI predictive models in drug screening and for risk assessment of industrial chemicals.
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration , 3900 NCTR RD, Jefferson, Arkansas 72079, United States.
authors.forename: Leihong
authors.initials: L
authors.lastname: Wu
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration , 3900 NCTR RD, Jefferson, Arkansas 72079, United States.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences , 111 T.W. Alexander Drive, RTP, North Carolina 27709, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Auerbach
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration , 3900 NCTR RD, Jefferson, Arkansas 72079, United States.
authors.forename: Minjun
authors.initials: M
authors.lastname: Chen
authors.affiliation: University of Arkansas at Little Rock , 2801 S University Ave, Little Rock, Arkansas 72204, United States.
authors.forename: Kristin
authors.initials: K
authors.lastname: McEuen
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration , 3900 NCTR RD, Jefferson, Arkansas 72079, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Xu
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration , 3900 NCTR RD, Jefferson, Arkansas 72079, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Fang
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration , 3900 NCTR RD, Jefferson, Arkansas 72079, United States.
authors.forename: Weida
authors.identifier: 0000-0002-4093-3708
authors.initials: W
authors.lastname: Tong
mesh_terms: D056486:Chemical and Drug Induced Liver Injury; D019295:Computational Biology / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations