Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substrate selectivity.
The UDP-glucuronosyltransferase (UGT) enzyme 'superfamily' contributes to the metabolism of a myriad of drugs, nondrug xenobiotic agents, and endogenous compounds. Although the individual UGT isoforms exhibit distinct but overlapping substrate selectivities, structural features of substrates that confer selectivity remain largely unknown. Using methods developed for pharmacophore fingerprinting combined with optimization and pattern recognition techniques, subsets of pharmacophores associated with the substrates and nonsubstrates of 12 human UGT isoforms were selected to generate predictive models of substrate selectivity and to elucidate the chemical and structural features associated with substrates and nonsubstrates. For all 12 UGT isoforms, the pharmacophore model generated showed predictive ability, as determined by a test set comprising 30% of the available data for each isoform. Models for UGT1A6, -1A7, -1A9, and -2B4 displayed the best predictive ability (>75% of test set predicted correctly) and were further analyzed to interpret the pharmacophores selected as important. The individual pharmacophores differed among isoforms but generally represented relatively simple structural and chemical features. For example, an aromatic ring attached to the nucleophilic group was found to increase the likelihood of glucuronidation by UGT1A6, UGT1A7 and UGT1A9. A large hydrophobic region close to the nucleophile and a hydrogen bond acceptor 10 A from the nucleophile were found to be common to most UGT2B4 substrates. The pharmacophores further suggest that the environment immediately adjacent to the nucleophilic site of conjugation is an important determinant of metabolism by a particular UGT.
Sorich
Michael J
MJ
School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, Adelaide, Australia.
Miners
John O
JO
McKinnon
Ross A
RA
Smith
Paul A
PA
D014453:Glucuronosyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000502:physiology; D000090264:UDP-Glucuronosyltransferase 1A9
D007527:Isoenzymes; C000715591:UGT1A9 protein, human; C110655:UDP-glucuronosyltransferase, UGT1A6; C113480:UGT2B11 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C107611:UDP-glucuronosyltransferase, UGT1A7; C486404:UGT2B4 protein, human