title: Human nephrotoxicity prediction models for three types of kidney injury based on data sets of pharmacological compounds and their metabolites.
abstract: The kidney is the most important organ for the excretion of pharmaceuticals and their metabolites. Among the complex structures of the kidney, the proximal tubule and renal interstitium are major targets of nephrotoxins. Despite its importance, there are only a few in silico models for predicting human nephrotoxicity for drug candidates. Here, we present quantitative structure-activity relationship (QSAR) models for three common patterns of drug-induced kidney injury, i.e., tubular necrosis, interstitial nephritis, and tubulo-interstitial nephritis. A support vector machine (SVM) was used to build the binary classification models of nephrotoxin versus non-nephrotoxin with eight fingerprint descriptors. To build the models, we constructed two types of data sets, i.e., parent compounds of pharmaceuticals (251 nephrotoxins and 387 non-nephrotoxins) and their major urinary metabolites (307 nephrotoxins and 233 non-nephrotoxins). Information on the nephrotoxicity of the pharmaceuticals was taken from clinical trial and postmarketing safety data. Though the mechanisms of nephrotoxicity are very complex, by using the metabolite information, the predictive accuracies of the best models for each type of kidney injury were better than 83% for external validation sets. Software to predict nephrotoxicity is freely available from our Web site at http://bmdrc.org/DemoDownload .
authors.affiliation: Bioinformatics and Molecular Design Research Center , Seoul 120-749, Korea.
authors.forename: Sehan
authors.initials: S
authors.lastname: Lee
authors.forename: Young-Mook
authors.initials: YM
authors.lastname: Kang
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Dong
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Shin
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
mesh_terms: D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D020407:Internet; D007668:Kidney / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism* / Q000652:urine; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D060388:Support Vector Machine; D014584:User-Computer Interface
chemical_list: D004364:Pharmaceutical Preparations