title: Experimental determination and prediction of bilitranslocase transport activity.
abstract: The transport activity of a membrane protein, bilitranslocase (T.C. # 2.A.65.1.1), which acts as a transporter of bilirubin from blood to liver cells, was experimentally determined for a large set of various endogenous compounds, drugs, purine and pyrimidine derivatives. On these grounds, the structure-activity models were developed following the OECD principles of QSAR models and their predictive ability for new chemicals was evaluated. The applicability domain of the models was estimated by Euclidean distances criteria according to the applied modeling method. The selection of the most influential structural variables was an important stage in the adopted modeling methodology. The interpretation of selected variables was performed in order to get an insight into the mechanism of transport through the cell membrane via bilitranslocase. Validation of the optimized models was performed by a previously determined validation set. The classification model was build to separate active from inactive compounds. The resulting accuracy, sensitivity, and specificity were 0.73, 0.89, and 0.64, respectively. Only active compounds were used to develop a predictive model for bilitranslocase inhibition constants. The model showed good predictive ability; Root Mean Squared error of the validation set, RMS(V)=0.29 log units.
authors.affiliation: Laboratory of Chemometrics, National Institute of Chemistry, Hajdrihova 19, SI-1115 Ljubljana, Slovenia. spela.zuperl@ki.si
authors.forename: Špela
authors.initials: Š
authors.lastname: Župerl
authors.forename: Stefano
authors.initials: S
authors.lastname: Fornasaro
authors.forename: Marjana
authors.initials: M
authors.lastname: Novič
authors.forename: Sabina
authors.initials: S
authors.lastname: Passamonti
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002570:Ceruloplasmin; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008565:Membrane Proteins; D004364:Pharmaceutical Preparations; D011687:Purines; D011743:Pyrimidines; D002570:Ceruloplasmin; C033838:bilitranslocase