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Research ArticleArticle

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

P. N. Palma, M. J. Bonifácio, A. I. Loureiro, L. C. Wright, D. A. Learmonth and P. Soares-da-Silva
Drug Metabolism and Disposition March 2003, 31 (3) 250-258; DOI: https://doi.org/10.1124/dmd.31.3.250
P. N. Palma
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M. J. Bonifácio
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A. I. Loureiro
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L. C. Wright
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D. A. Learmonth
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P. Soares-da-Silva
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Abstract

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3–202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3–202 within the active site of COMT and discuss their implication on the regioselectivity of metabolicO-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity ofO-methylation of BIA 3–202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivoO-methylation by COMT at either meta orpara catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, thep-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolicO-methylation are discussed.

Footnotes

  • Supported in part by grant P003-P31B-02/97 BIAL-COMT from Agência de Inovação.

  • Abbreviations used are::
    COMT
    catechol-O-methyltransferase
    l-DOPA
    l-3,4-dihydroxyphenylalanine
    AdoMet
    S-adenosyl-l-methionine
    BIA 3–202
    1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone
    S-COMT
    soluble form of rat COMT
    3,5-DNC
    (OR-486) 3,5-dinitrocatechol
    Tolcapone
    (RO 40–7592) 3,4-dihydroxy-4′-methyl-5-nitrobenzophenone
    BIA 3–270 (meta-O-methylated metabolite)
    1-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-phenyl-ethanone
    BIA 3–449 (para-O-methylated metabolite)
    1-(3-hydroxy-4-methoxy-5-nitrophenyl)-2-phenyl-ethanone
    3,5-DNC
    3,5-dinitrocatechol
    • Received October 4, 2002.
    • Accepted November 21, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (3)
Drug Metabolism and Disposition
Vol. 31, Issue 3
1 Mar 2003
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Research ArticleArticle

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

P. N. Palma, M. J. Bonifácio, A. I. Loureiro, L. C. Wright, D. A. Learmonth and P. Soares-da-Silva
Drug Metabolism and Disposition March 1, 2003, 31 (3) 250-258; DOI: https://doi.org/10.1124/dmd.31.3.250

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Research ArticleArticle

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

P. N. Palma, M. J. Bonifácio, A. I. Loureiro, L. C. Wright, D. A. Learmonth and P. Soares-da-Silva
Drug Metabolism and Disposition March 1, 2003, 31 (3) 250-258; DOI: https://doi.org/10.1124/dmd.31.3.250
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