Pharmacophore and quantitative structure-activity relationship modeling: complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity.
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.
Smith
Paul A
PA
Department of Clinical Pharmacology, Flinders University, Bedford Park, 5042, South Australia. paul.smith@flinders.edu.au
Sorich
Michael J
MJ
McKinnon
Ross A
RA
Miners
John O
JO
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
D020719:Glucuronides; D007527:Isoenzymes; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase