Inhibition of Bilirubin UDP‐glucuronosyltransferase: A Comparative Molecular Field Analysis (CoMFA)

Said, Mourad; Ziegler, Jean-Claude; Magdalou, Jacques; Elass, Abdelaziz; Vergoten, G.

doi:10.1002/qsar.19960150503

Cited by 13 publications

(10 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These compounds are also substrates for purified rat liver bilirubin UGT, indicating productive binding within the active site [113]. Said et al [116] performed a three-dimensional quantitative structure-activity relationship study on two series of rat liver bilirubin-UGT inhibitors derived from phenolphthalein and triphenylalkyl carboxylic acids. In addition to providing a predictive model for the inhibitory potency of new compounds, three-dimensional steric and electrostatic contour maps were described in this work Drug Metabolism Reviews Downloaded from informahealthcare.com by University of Sussex Library on 10/25/12…”

Section: Figmentioning

confidence: 97%

Structural and Functional Studies of Udp-Glucuronosyltransferases*

Radominska‐Pandya

Czernik

Little

et al. 1999

Drug Metabolism Reviews

446

358

View full text Add to dashboard Cite

UDP-Glucuronosyltransferases (UGTs) are glycoproteins localized in the endoplasmic reticulum (ER) which catalyze the conjugation of a broad variety of lipophilic aglycon substrates with glucuronic acid using UDP-glucuronic acid (UDP-GIcUA) as the sugar donor. Glucuronidation is a major factor in the elimination of lipophilic compounds from the body. In this review, current information on the substrate specificities of UGT1A and 2B family isoforms is discussed. Recent findings with regard to UGT structure and topology are presented, including a dynamic topological model of UGTs in the ER. Evidence from experiments on UGT interactions with inhibitors directed at specific amino acids, photoaffinity labeling, and analysis of amino acid alignments suggest that UDP-GIcUA interacts with residues in both the N- and C-terminal domains, whereas aglycon binding sites are localized in the N-terminal domain. The amino acids identified so far as crucial for substrate binding and catalysis are arginine, lysine, histidine, proline, and residues containing carboxylic acid. Site-directed mutagenesis experiments are critical for unambiguous identification of the active-site architecture.

show abstract

Section: Figmentioning

confidence: 97%

Structural and Functional Studies of Udp-Glucuronosyltransferases*

Radominska‐Pandya

Czernik

Little

et al. 1999

Drug Metabolism Reviews

446

358

View full text Add to dashboard Cite

show abstract

“…However, attempts to develop predictive QSAR for substrates of UGT1A9 have been unsuccessful . On the other hand, CoMFA was used to examine a series of 18 compounds (triphenylalkyl carboxylic acid analog) that inhibited glucuronidation of bilirubin by UGT1A1; the resulting model allowed good prediction of inhibitory potency (Said et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Quantitative Structure-Activity Relationship Studies on UGT1A9-Mediated 3-O-Glucuronidation of Natural Flavonols Using a Pharmacophore-Based Comparative Molecular Field Analysis Model

Morrow

Singh

et al. 2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., K m , V max , intrinsic clearance (CL int ) ϭ V max /K m ] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters (K m , V max , CL int ) were obtained. The observed K m , V max , and CL int values of 3-O-glucuronidation ranged from 0.04 to 0.68 M, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of V max and CL int , respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (V max model: q 2 ϭ 0.738, r 2 ϭ 0.976, r pred 2 ϭ 0.735; CL int model: q 2 ϭ 0.561, r 2 ϭ 0.938, r pred 2 ϭ 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.

show abstract

“…This kinetic study was performed with rat liver microsomes, thus providing an intact environment for a fully active enzyme. This model is therefore suitable to perform structure-activity relationships (37). Attempts to purify the enzyme led to a very unstable protein due to its strict phospholipid requirement.…”

Section: Discussionmentioning

confidence: 99%