Molecular Modeling and Metabolic Studies of The Interaction of Catechol-<i>O</i>-Methyltransferase and a New Nitrocatechol Inhibitor

Palma, P. Nuno; Bonifácio, Maria João; Loureiro, Ana; Wright, Lyndon; Learmonth, David A.; Soares-da-Silva, Patrı́cio

doi:10.1124/dmd.31.3.250

Cited by 40 publications

(29 citation statements)

References 34 publications

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Section: Role Of Comt In Disposition Of Luteolin In Ratsmentioning

confidence: 55%

“…Such different regioselectivities of O-methylation by COMT in in vivo versus in vitro conditions were previously reported for other sub- strates but not clearly explained (Palma et al, 2003). We supposed that further metabolism might cause different degradation of each metabolite (Palma et al, 2003). For example, some cytochrome P450s, such as CYP1A and CYP2C, selectively demethylate the 4-O-methyl (Busse et al, 1995;Androutsopoulos et al, 2010), which may result in accumulation of 3-O-methylation in vivo.…”

Section: Role Of Comt In Disposition Of Luteolin In Ratsmentioning

confidence: 74%

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Role of Catechol-O-Methyltransferase in the Disposition of Luteolin in Rats

Chen¹,

Chen²,

Pan³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Luteolin is mainly metabolized by phase II enzymes in animals and humans with glucuronidation and sulfation as the two known metabolic pathways. Although methylation of luteolin was reported previously, the structure of the methylated metabolites and the enzymes involved in the process have not been clarified. In our study, two methylated metabolites, M1 (chrysoeriol) and M2 (diosmetin), were identified in the urine after intravenous administration of luteolin to rats, and the data suggested that the methylation was mediated by catechol-O-methyltransferase (COMT). When luteolin was coadministered with a specific COMT inhibitor, entacapone, the formation of M1 and M2 was significantly reduced, whereas the plasma concentration of luteolin increased. Methylation of luteolin was also studied in vitro using rat tissue homogenates. The apparent kinetic parameters associated with the formation of M1 and M2 in vitro were estimated, and regioselectivity of methylation of luteolin was observed. In the in vitro experiment, there was a preference for the formation of M2 over M1. In contrast, accumulation of M1 was preferred in vivo in both rat plasma and urine after an intravenous dose of luteolin. In conclusion, COMT played a crucial role in the disposition of luteolin in rats. Our results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor. Therefore, COMT-associated drug-drug interactions need be considered in the future in luteolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitor.

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Section: Role Of Comt In Disposition Of Luteolin In Ratsmentioning

confidence: 55%

Section: Role Of Comt In Disposition Of Luteolin In Ratsmentioning

confidence: 74%

Role of Catechol-O-Methyltransferase in the Disposition of Luteolin in Rats

Chen¹,

Chen²,

Pan³

et al. 2011

Drug Metab Dispos

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“…However, depending on the nature of substituent(s), the catechol ring may be forced into one of two opposite orientations, thereby determining which of the two catechol hydroxyl groups (either the 3-or 4-hydroxyl) is exposed to the methyl donor cosubstrate. Catecholamines and many other catechol substrates have been shown to undergo preferential 3-O-methylation (Creveling et al, 1972;Thakker et al, 1986;Lotta et al, 1995), which can be explained in terms of the structure and interactions of the catechol ring substituents with the catalytic site residues (Lotta et al, 1995;Lau and Bruice, 1998;Palma et al, 2003). The regioselectivity of O-methylation, however, is not restricted to the substrates of COMT.…”

mentioning

confidence: 99%

“…The regioselectivity of O-methylation, however, is not restricted to the substrates of COMT. Typical nitrocatecholic COMT inhibitors, although poor substrates of the enzyme, may also be partially Omethylated by COMT, originating mono-O-methyl ether derivatives (Da Prada et al, 1994;Dingemanse et al, 1996;Palma et al, 2003). Likewise, how does the structure of the inhibitor affect the regioselectivity of its enzymatically catalyzed O-methylation?…”

mentioning

confidence: 99%

Comparative Study ofortho-andmeta-Nitrated Inhibitors of Catechol-O-methyltransferase: Interactions with the Active Site and Regioselectivity ofO-Methylation

Palma¹,

Rodrigues²,

Archer³

et al. 2006

Mol Pharmacol

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In this work, we present a comparative case study of "ortho-" and "meta-nitrated" catecholic inhibitors of catechol-O-methyltransferase (COMT), with regard to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. In particular, the effects of altering the attachment position of the inhibitors' side-chain substituent, within the classic nitrocatechol pharmacophore, were investigated. For this purpose, we compared two simple regioisomeric nitrocatechol-type inhibitors of COMT, BIA 3-228 and BIA 8-176, which contain the benzoyl substituent attached at the meta and ortho positions, respectively, relative to the nitro group. The two compounds were slowly O-methylated by COMT in vitro, but the particular substitution pattern of each compound was shown to have a profound impact on the regioselectivity of their O-methylation.To provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and ab initio molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation were identified, and the X-ray structure of the complex of COMT with S-adenosyl-Lmethionine and BIA 8-176 is herein disclosed. This is the first reported structure of the soluble form of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in adjacent position (ortho) to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study.

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“…This has mostly, however, been simulations using the QM-MM method (Quantum Mechanics-Molecular Mechanics) to focus on the details of the catalytic reaction itself [10][11][12][13][14][15] or QSAR-type analysis [16]. In addition to the interest in the activity and …”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations of the enzyme Catechol-O-Methyltransferase: methodological issues

Bunker

Männistö

Pierre

et al. 2008

SAR and QSAR in Environmental Research

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Results from extensive 70 ns all-atom molecular dynamics simulations of catechol-Omethyltransferase (COMT) enzyme are reported. The simulations were performed with explicit TIP3P water and Mg 2þ ions. Four different crystal structures of COMT, with and without different ligands, were used. These simulations are among the most extensive of their kind and as such served as a stability test for such simulations. On the methodological side we found that the initial energy minimization procedure may be a crucial step: particular hydrogen bonds may break, and this can initiate an irreversible loss of protein structure that becomes observable in longer time scales of the order of tens of nanoseconds. This has important implications for both molecular dynamics and quantum mechanics-molecular mechanics simulations.

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Molecular Modeling and Metabolic Studies of The Interaction of Catechol-O-Methyltransferase and a New Nitrocatechol Inhibitor

Cited by 40 publications

References 34 publications

Role of Catechol-O-Methyltransferase in the Disposition of Luteolin in Rats

Role of Catechol-O-Methyltransferase in the Disposition of Luteolin in Rats

Comparative Study ofortho-andmeta-Nitrated Inhibitors of Catechol-O-methyltransferase: Interactions with the Active Site and Regioselectivity ofO-Methylation

Molecular dynamics simulations of the enzyme Catechol-O-Methyltransferase: methodological issues

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