title: Pharmacophore and quantitative structure-activity relationship modeling: complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity.
abstract: Pharmacophore, two-dimensional (2D), and three-dimensional (3D) quantitative structure-activity relationship (QSAR) modeling techniques were used to develop and test models capable of rationalizing and predicting human UDP-glucuronosyltransferase 1A4 (UGT1A4) substrate selectivity and binding affinity (as K(m,app)). The dataset included 24 structurally diverse UGT1A4 substrates, with 18 of these comprising the training set and 6 an external prediction set. A common features pharmacophore was generated with the program Catalyst after overlapping the sites of conjugation using a novel, user-defined "glucuronidation" feature. Pharmacophore-based 3D-QSAR (r(2) = 0.88) and molecular-field-based 3D-QSAR (r(2) = 0.73) models were developed using Catalyst and self-organizing molecular field analysis (SOMFA) software, respectively. In addition, a 2D-QSAR (r(2) = 0.80, CV r(2) = 0.73) was generated using partial least-squares (PLS) regression and variable selection using an unsupervised forward selection (UFS) algorithm. Both UGT1A4 pharmacophores included two hydrophobic features and the glucuronidation site. The 2D-QSAR showed the best overall predictivity and highlighted the importance of hydrophobicity (as log P) in substrate-enzyme binding.
authors.affiliation: Department of Clinical Pharmacology, Flinders University, Bedford Park, 5042, South Australia. paul.smith@flinders.edu.au
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sorich
authors.forename: Ross A
authors.initials: RA
authors.lastname: McKinnon
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D002384:Catalysis; D020719:Glucuronides / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D020719:Glucuronides; D007527:Isoenzymes; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase