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Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation.

Palma PN, Rodrigues ML, Archer M, Bonifácio MJ, Loureiro AI, Learmonth DA, Carrondo MA, Soares-da-Silva P
Mol Pharmacol 70 143-53 (2006)
Cited: 26 times
EuropePMC logo PMID: 16618795

Abstract

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-l-methionine 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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  2. Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders. Ma Z, Liu H, Wu B. Br J Clin Pharmacol 77 410-420 (2014)
  3. Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches. Cruz-Vicente P, Passarinha LA, Silvestre S, Gallardo E. Molecules 26 2193 (2021)

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  1. Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. Kinnings SL, Liu N, Buchmeier N, Tonge PJ, Xie L, Bourne PE. PLoS Comput Biol 5 e1000423 (2009)
  2. Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling. Pantsar T, Rissanen S, Dauch D, Laitinen T, Vattulainen I, Poso A. PLoS Comput Biol 14 e1006458 (2018)
  3. The crystal structure of the novobiocin biosynthetic enzyme NovP: the first representative structure for the TylF O-methyltransferase superfamily. Gómez García I, Stevenson CE, Usón I, Freel Meyers CL, Walsh CT, Lawson DM. J Mol Biol 395 390-407 (2010)
  4. Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases. Trievel RC, Scheiner S. Molecules 23 E2965 (2018)


Reviews citing this publication (1)

  1. Catechol-O-methyltransferase and its inhibitors in Parkinson's disease. Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P. CNS Drug Rev 13 352-379 (2007)

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  1. Crystal structures of human 108V and 108M catechol O-methyltransferase. Rutherford K, Le Trong I, Stenkamp RE, Parson WW. J Mol Biol 380 120-130 (2008)
  2. How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O-Methyltransferase. Kulik HJ, Zhang J, Klinman JP, Martínez TJ. J Phys Chem B 120 11381-11394 (2016)
  3. Structure and mechanism of the rebeccamycin sugar 4'-O-methyltransferase RebM. Singh S, McCoy JG, Zhang C, Bingman CA, Phillips GN, Thorson JS. J Biol Chem 283 22628-22636 (2008)
  4. Computation of the binding affinities of catechol-O-methyltransferase inhibitors: multisubstate relative free energy calculations. Palma PN, Bonifácio MJ, Loureiro AI, Soares-da-Silva P. J Comput Chem 33 970-986 (2012)
  5. Tau-derived-hexapeptide 306VQIVYK311 aggregation inhibitors: nitrocatechol moiety as a pharmacophore in drug design. Mohamed T, Hoang T, Jelokhani-Niaraki M, Rao PP. ACS Chem Neurosci 4 1559-1570 (2013)
  6. Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase. Law BJ, Bennett MR, Thompson ML, Levy C, Shepherd SA, Leys D, Micklefield J. Angew Chem Int Ed Engl 55 2683-2687 (2016)
  7. Methylation of catechins and procyanidins by rat and human catechol-O-methyltransferase: metabolite profiling and molecular modeling studies. Weinert CH, Wiese S, Rawel HM, Esatbeyoglu T, Winterhalter P, Homann T, Kulling SE. Drug Metab Dispos 40 353-359 (2012)
  8. Molecular recognition at the active site of catechol-o-methyltransferase: energetically favorable replacement of a water molecule imported by a bisubstrate inhibitor. Ellermann M, Jakob-Roetne R, Lerner C, Borroni E, Schlatter D, Roth D, Ehler A, Rudolph MG, Diederich F. Angew Chem Int Ed Engl 48 9092-9096 (2009)
  9. Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors. Ellermann M, Lerner C, Burgy G, Ehler A, Bissantz C, Jakob-Roetne R, Paulini R, Allemann O, Tissot H, Grünstein D, Stihle M, Diederich F, Rudolph MG. Acta Crystallogr D Biol Crystallogr 68 253-260 (2012)
  10. Structural characterization of the mitomycin 7-O-methyltransferase. Singh S, Chang A, Goff RD, Bingman CA, Grüschow S, Sherman DH, Phillips GN, Thorson JS. Proteins 79 2181-2188 (2011)
  11. Convergent Mechanistic Features between the Structurally Diverse N- and O-Methyltransferases: Glycine N-Methyltransferase and Catechol O-Methyltransferase. Zhang J, Klinman JP. J Am Chem Soc 138 9158-9165 (2016)
  12. Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase. Patra N, Ioannidis EI, Kulik HJ. PLoS One 11 e0161868 (2016)
  13. Molecular architecture and structural basis of allosteric regulation of eukaryotic phosphofructokinases. Sträter N, Marek S, Kuettner EB, Kloos M, Keim A, Brüser A, Kirchberger J, Schöneberg T. FASEB J 25 89-98 (2011)
  14. Biosynthesis of mycobacterial methylmannose polysaccharides requires a unique 1-O-methyltransferase specific for 3-O-methylated mannosides. Ripoll-Rozada J, Costa M, Manso JA, Maranha A, Miranda V, Sequeira A, Ventura MR, Macedo-Ribeiro S, Pereira PJB, Empadinhas N. Proc Natl Acad Sci U S A 116 835-844 (2019)
  15. Investigation of the Molecular Mechanisms of Antioxidant Damage and Immune Response Downregulation in Liver of Coilia nasus Under Starvation Stress. Wang M, Xu G, Tang Y, Su S, Wang Y, Zhu Z. Front Endocrinol (Lausanne) 12 622315 (2021)
  16. Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson's Disease: Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies. Cruz-Vicente P, Gonçalves AM, Ferreira O, Queiroz JA, Silvestre S, Passarinha LA, Gallardo E. Pharmaceuticals (Basel) 15 51 (2021)
  17. Ground- and excited-state stability of the conformers of 3,5-dinitrocatechol and its complexes with W(VI) and V(V): combined theoretical and experimental study. Delchev VB, Gavazov KB, Shterev IG. J Mol Model 20 2549 (2014)
  18. Investigating Paracetamol's Role as a Potential Treatment for Parkinson's Disease: Ab Initio Analysis of Dopamine, l-DOPA, Paracetamol, and NAPQI Interactions with Enzymes Involved in Dopamine Metabolism. Harle J, Slater C, Cafiero M. ACS Omega 8 38053-38063 (2023)


Related citations provided by authors (1)

  1. Crystallization and preliminary X-ray diffraction studies of a catechol-O-methyltransferase/inhibitor complex.. Rodrigues ML, Bonifácio MJ, Soares-da-Silva P, Carrondo MA, Archer M Acta Crystallogr Sect F Struct Biol Cryst Commun 61 118-20 (2005)

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