Multiple Pharmacophores for the Investigation of Human UDP-Glucuronosyltransferase Isoform Substrate Selectivity

Abstract

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 (Ͼ75% 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 Å 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.

Deferiprone Glucuronidation by Human Tissues and Recombinant UDP Glucuronosyltransferase 1A6: An in Vitro Investigation of Genetic and Splice Variants

“…UGT1A6 has been demonstrated to have a particular affinity for substrates containing a nucleophile attached to an aromatic ring (Sorich et al, 2004), which is consistent with the chemical structure of deferiprone (Fig. 2).…”

Glycosidation of an Endothelin ETA Receptor Antagonist and Diclofenac in Human Liver Microsomes: Aglycone-dependent UDP-sugar Selectivity

“…Although conformational changes induced by aglycone binding to UGT2B7 are postulated to contribute to altered sugar donor selectivity, a full understanding of the mechanism is awaiting the availability of the crystal structure of UGT2B7. However, computational methodologies have been developed to predict acceptor substrate selectivity and to provide a measure of substrate binding (Smith et al, 2003Sorich et al, 2002Sorich et al, , 2004. Therefore, with this approach, compounds known to have the ability to change sugar donor selectivity could be utilized for further investigation of the properties of the corresponding UGTs.…”

Evaluation of 5-Hydroxytryptophol and Other Endogenous Serotonin (5-Hydroxytryptamine) Analogs as Substrates for Udp-Glucuronosyltransferase 1a6

“…pharmacophore structure-activity modeling approach suggests that the presence of a hydrophilic group on the substrate molecule 6 Å distance from the nucleophilic conjugation site negatively impacts the likelihood of glucuronidation by UGT1A6 (Sorich et al, 2004). Whether the indolealkyl side chain carboxyl group that we have identified represents such an inhibitory moiety would need to be confirmed by the use of similar sophisticated molecular modeling techniques.…”