Pedro Nuno Palma *

Autor invitado por SIIC

FACTORES QUE CONTROLAM A INACTIVAÇÃO METABOLICA DE INIBIDORES DA COMT, POR O-METILAÇÃO

Exploramos os efeitos de alterações estruturais em inibidores da COMT, sobre a sua interacção molecular com o centro catalítico da enzima e sobre a regioselectividade da reacção de O-metilação dos mesmos. É apresentada e discutida a estrutura cristalográfica do complexo entre a COMT e um desses inibidores.

*Pedro Nuno Palma
describe para SIIC los aspectos relevantes de su trabajo
COMPARATIVE STUDY OF ORTHO- AND META-NITRATED INHIBITORS OF CATECHOL-O-METHYLTRANSFERASE: INTERACTIONS WITH THE ACTIVE SITE AND REGIOSELECTIVITY OF O-METHYLATION
Institución principal de la investigación
*BIAL, S. Mamede do Coronado, Trofa, Portugal
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Otros artículos escogidos

Referencias bibliográficas
1. Bonifácio MJ, Archer M, Rodrigues ML, Matias PM, Learmonth DA, Carrondo MA, Soares Da Silva P. Kinetics and crystal structure of catechol-O-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application. Molecular Pharmacology 2002; 62:795-805.
2. Bonifacio MJ, Vieira Coelho MA, Soares Da Silva P. Kinetic inhibitory profile of BIA 3-202, a novel fast tight-binding, reversible and competitive catechol-O-methyltransferase inhibitor. European Journal of Pharmacology 2003; 460:163-70.
3. Bonifati V, Meco G. New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson's disease. Pharmacology & Therapeutics 1999; 81:1-36.
4. Fukui K, Yonezawa T, Nagata C. Theory of substitution in conjugated molecules. Bulletin of the Chemical Society of Japan 1954; 27:423-427.
5. Jones G, Willett P, Glen RC. A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. Journal of Computer-Aided Molecular Design 1995; 9:532-49.
6. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology 1997; 267:727-48.
7. Kellogg GE, Joshi GS, Abraham DJ. New tools for modeling and understanding hydrophobicity and hydrophobic interactions. Medicinal Chemistry Reviews 1992; 1:444-453.
8. Kuhn B, Kollman PA. QM-FE and molecular dynamics calculations on catechol-O-methyltransferase: Free energy of activation in the enzyme and in aqueous solution and regioselectivity of the enzyme-catalyzed reaction. Journal of the American Chemical Society 2000; 122:2586-2596.
9. Lau EY, Bruice TC. Importance of correlated motions in forming highly reactive near attack conformations in catechol-O-methyltransferase. Journal of the American Chemical Society 1998; 120:12387-12394.
10. Learmonth DA, Bonifacio MJ, Soares Da Silva P. Synthesis and biological evaluation of a novel series of "Ortho-Nitrated" inhibitors of catechol-O-methyltransferase. Journal of Medicinal Chemistry 2005; 48, 8070-8.
11. Learmonth DA, Palma PN, Vieira Coelho MA, Soares da Silva P. Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase. Journal of Medicinal Chemistry 2004; 47:6207-17.
12. Learmonth DA, Vieira Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, Soares da Silva P. Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase. Journal of Medicinal Chemistry 2002; 45, 685-95.
13. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J. Kinetics of human soluble and membrane-bound catechol-O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34:4202-10.
14. Männistö PT, Kaakkola S. New selective COMT inhibitors: useful adjuncts for Parkinson's disease? Trends in Pharmacological Sciences 1989; 10:54-6.
15. Männistö PT, Kaakkola S. Rationale for selective COMT inhibitors as adjuncts in the drug treatment of Parkinson's disease. Pharmacology & Toxicology 1990; 66:317-23.
16. Palma PN, Bonifacio MJ, Loureiro AI, Wright LC, Learmonth DA, Soares Da Silva P. Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor. Drug Metabolism and Disposition 2003; 31:250-8.
17. Rodrigues ML, Bonifacio MJ, Soares da Silva P, Carrondo MA, Archer M. Crystallisation and preliminary X-ray diffraction studies of a catechol-O-methyltransferase/inhibitor complex. Acta Crystallographica Section D: Biological Crystallography 2005; F61:118-120.
18. Vidgren J, Svensson LA, Liljas A. Crystal structure of catechol-O-methyltransferase. Nature 1994; 368:354-8.
19. Zheng YJ, Bruice TC. A Theoretical examination of the factors controlling the catalytic efficiency of a transmethylation enzyme - Catechol-O-methyltransferase. Journal of the American Chemical Society 1997; 119:8137-8145.

Otros artículos de Pedro Nuno Palma

Palma PN, Rodrigues ML, Archer M, Bonifácio MJ, Loureiro AI, Learmonth DA, Carrondo MA, Soares da Silva P. Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: Interactions with the active site and regioselectivity of O-methylation. Mol Pharmacol 2006; 70(1):143-153.
Palma PN, Bonifácio MJ, Loureiro AI, Wright IC, Learmonth DA, Soares da Silva P. Molecular modeling and metabolic studies of the interaction of catechol-o-methyltransferase and a new nitrocatechol inhibitor. Drug Metabolism and Disposition 2003; 31(3):250-258.
Learmonth DA, Palma PN, Vieira Coelho MA, Soares da Silva P. Synthesis, biological evaluation and molecular modeling studies of a novel, peripherally-selective inhibitor of catechol-O-methyltransferase. J Med Chem 2004; 47(25):6207-6217.
Palma PN, Krippahl L, Wampler JE, Moura JJ. BiGGER: a new (soft) docking algorithm for predicting protein interactions. Proteins: Structure, Function and Genetics 2000; 39:372-84.
Krippahl L, Moura JJ, Palma PN. Modeling protein complexes with BiGGER. Proteins 2003; 52:19-23.
Palma PN, Lagoutte B, Krippahl L, Moura JJ, Guerlesquin F. Synechocystis ferredoxin/ferredoxin-NADP(+)-reductase/NADP+ complex: Structural model obtained by NMR-restrained docking. FEBS 2005; Lett 579, 4585-90.
Morelli XJ, Palma PN, Guerlesquin F, Rigby AC. A novel approach for assessing macromolecular complexes combining soft docking calculations with NMR data. Protein Science 2001; 10:2131-37.
Morelli X, Dolla A, Czjzek M, Palma PN, Blasco F, Krippahl L, Moura JJ, Guerlesquin F. Heteronuclear NMR and soft docking: an experimental approach for a structural model of the cytochrome c553 / ferredoxin complex. Biochemistry 2000; 39(10):2530-2537.
Domingos A, Grancho AP, Iley J, Moreira R, Neres J, Palma PN, Santana AB, Valente E. Design, synthesis and stability of N-acyloxymethyl- and N-aminocarbonyloxymethyl-2-azetidinones as human leukocyte elastase inhibitors. Bioorg Med Chem Lett 2001; 11:1065-68.
Palma PN, Moura I, LeGall J, Van Beeumen J, Wampler JE, Moura JJ. Evidence for a ternary complex formed between flavodoxin and cytochrome c3: 1H-NMR and molecular modeling studies. Biochemistry 1994; 33: 6394-407.

Para comunicarse con Pedro Nuno Palma mencionar a SIIC como referencia:
nuno.palma@bial.com

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Acerca del trabajo completo

FACTORES QUE CONTROLAM A INACTIVAÇÃO METABOLICA DE INIBIDORES DA COMT, POR O-METILAÇÃO

Título original en castellano
ESTUDO COMPARATIVO DE INIBIDORES ORTO- E META-NITRADOS DA CATECOL-O-METHYLTRANSFERASE: INTERACÇÕES COM O CENTRO ACTIVO E REGIOSELECTIVIDADE DE O-METILAÇÃO

Autores
Pedro Nuno Palma¹, Maria Luísa Rodrigues², Maria João Bonifácio³, Ana Loureiro⁴, Ana Loureiro⁵, Maria Arménia Carrondo⁶, Patrício Soares da Silva⁷
1 Bioquímico, Department of Research & Development, BIAL, S. Mamede do Coronado, Trofa, Portugal
2, Instituto de Tecnilogia Química e Biológica, Oeiras, Portugal
3, Bial
4, Bial
5, Bial
6, Instituto de Tecnilogia Química e Biológica
7, Bial

Acceso a la fuente original
Molecular Pharmacology
http://molpharm.aspetjournals.org/

ua40317