Advertisement

Journal of Computer-Aided Molecular Design

, Volume 31, Issue 10, pp 905–913 | Cite as

Computational design of bio-inspired carnosine-based HOBr antioxidants

  • Farzaneh Sarrami
  • Li-Juan Yu
  • Amir Karton
Article

Abstract

During a respiratory burst the enzyme myeloperoxidase generates significant amounts of hypohalous acids (HOX, X = Cl and Br) in order to inflict oxidative damage upon invading pathogens. However, excessive production of these potent oxidants is associated with numerous inflammatory diseases. It has been suggested that the endogenous antioxidant carnosine is an effective HOCl scavenger. Recent computational and experimental studies suggested that an intramolecular Cl+ transfer from the imidazole ring to the terminal amine might play an important role in the antioxidant activity of carnosine. Based on high-level ab initio calculations, we propose a similar reaction mechanism for the intramolecular Br+ transfer in carnosine. These results suggest that carnosine may be an effective HOBr scavenger. On the basis of the proposed reaction mechanism, we proceed to design systems that share similar structural features to carnosine but with enhanced HOX scavenging capabilities for X = Cl and Br. We find that (i) elongating the β-alanyl-glycyl side chain by one carbon reduces the reaction barriers by up to 44%, and (ii) substituting the imidazole ring with strong electron-donating groups reduces the reaction barriers by similar amounts. We also show that the above structural and electronic effects are largely additive. In an antioxidant candidate that involves both of these effects the reaction barriers are reduced by 71%.

Keywords

Molecular design Antioxidant design Computational chemistry CCSD(T) G4(MP2) theory 

Notes

Acknowledgements

This work is dedicated to our colleague and friend Dr. Ming Wen Shi, who tragically passed away earlier this year. This research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Government. We also acknowledge the system administration support provided by the Faculty of Science at the University of Western Australia to the Linux cluster of the Karton group. We gratefully acknowledge the provision of an Australian Postgraduate Award (to F.S.), and an Australian Research Council (ARC) Discovery Early Career Researcher Award (to A.K., Project No. DE140100311). We would also like to thank the reviewers of the manuscript for their valuable comments and suggestions.

Supplementary material

10822_2017_60_MOESM1_ESM.pdf (259 kb)
Supplementary material 1 (PDF 259 KB)

References

  1. 1.
    van Dalen C, Whitehouse M, Winterbourn C, Kettle A (1997) Biochem J 327:487CrossRefGoogle Scholar
  2. 2.
    Slungaard A, Mahoney JR (1991) J Biol Chem 266:4903Google Scholar
  3. 3.
    Thomas EL, Fishman M (1986) J Biol Chem 261:9694Google Scholar
  4. 4.
    van der Veen BS, de Winther MP, Heeringa P (2009) Antioxid Redox Signal 11:2899CrossRefGoogle Scholar
  5. 5.
    Klebanoff SJ (2005) J Leukoc Biol 77:598CrossRefGoogle Scholar
  6. 6.
    Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Int J Biochem Cell Biol 39:44CrossRefGoogle Scholar
  7. 7.
    Yap YW, Whiteman M, Cheung NS (2007) Cell Signal 19:219CrossRefGoogle Scholar
  8. 8.
    Malle E, Marsche G, Arnhold J, Davies MJ (2006) Biochim Biophys Acta 1761:392CrossRefGoogle Scholar
  9. 9.
    Balaban RS, Nemoto S, Finkel T (2005) Cell 120:483CrossRefGoogle Scholar
  10. 10.
    Stocker R, Keaney JF Jr (2004) Physiol Rev 84:1381CrossRefGoogle Scholar
  11. 11.
    Wu W, Samoszuk MK, Comhair SAA, Thomassen MJ, Farver CF, Dweik RA, Kavuru MS, Erzurum SC, Hazen SL (2000) J Clin Invest 105:1455CrossRefGoogle Scholar
  12. 12.
    Aldridge RE, Chan T, van Dalen CJ, Senthilmohan R, Winn M, Venge P, Town GI, Kettle AJ (2002) Free Rad Biol Med 33:847CrossRefGoogle Scholar
  13. 13.
    Spry CJF (1988) Eosinophils: a comprehensive review, and guide to the scientific and medical literature. Oxford University Press, OxfordGoogle Scholar
  14. 14.
    Kaliyeva L, Zhumagali S, Akhmetova N, Karton A, O’Reilly RJ (2017) Int J Quantum Chem 117:e25319CrossRefGoogle Scholar
  15. 15.
    O’Reilly RJ, Karton A (2016) Int J Quantum Chem 116:52CrossRefGoogle Scholar
  16. 16.
    O’Reilly RJ, Karton A, Radom. L (2013) J Phys Chem A 117:460CrossRefGoogle Scholar
  17. 17.
    O’Reilly RJ, Karton A, Radom L (2012) Int J Quantum Chem 112:1862CrossRefGoogle Scholar
  18. 18.
    O’Reilly RJ, Karton A, Radom L (2011) J Phys Chem A 115:5496CrossRefGoogle Scholar
  19. 19.
    Sivey JD, Howell SC, Bean DJ, McCurry DL, Mitch WA, Wilson CJ (2013) Biochemistry 52:1260CrossRefGoogle Scholar
  20. 20.
    Pattison DI, Hawkins CL, Davies MJ (2009) Chem Res Toxicol 22:807CrossRefGoogle Scholar
  21. 21.
    Hawkins CL (2009) Free Radic Res 43:1147CrossRefGoogle Scholar
  22. 22.
    Davies MJ, Hawkins CL, Pattison DI, Rees MD (2008) Antioxid Redox Signal 10:1199CrossRefGoogle Scholar
  23. 23.
    Pattison DI, Davies MJ (2006) Curr Med Chem 13:3271CrossRefGoogle Scholar
  24. 24.
    Pattison DI, Davies MJ (2005) Biochemistry 44:7378CrossRefGoogle Scholar
  25. 25.
    Hawkins CL, Pattison DI, Davies MJ (2003) Amino Acids 25:259CrossRefGoogle Scholar
  26. 26.
    Pattison DI, Davies MJ (2004) Biochemistry 43:4799CrossRefGoogle Scholar
  27. 27.
    Thomas EL, Bozeman PM, Jefferson MM, King CC (1995) J Biol Chem 270:2906CrossRefGoogle Scholar
  28. 28.
    Carr AC, Winterbourn CC, van den Berg JJ (1996) Arch Biochem Biophys 327:227CrossRefGoogle Scholar
  29. 29.
    Vissers M, Carr A, Chapman A (1998) Biochem J 330:131CrossRefGoogle Scholar
  30. 30.
    Henderson JP, Byun J, Mueller DM, Heinecke JW (2001) Biochemistry 40:2052CrossRefGoogle Scholar
  31. 31.
    Henderson JP, Byun J, Williams MV, McCormick ML, Parks WC, Ridnour LA, Heinecke JW (2001) Proc Natl Acad Sci USA 98:1631CrossRefGoogle Scholar
  32. 32.
    Drozak J, Veiga-da-Cunha M, Vertommen D, Stroobant V, Van Schaftingen E (2010) J Biol Chem 285:9346CrossRefGoogle Scholar
  33. 33.
    Quinn PJ, Boldyrev AA, Formazuyk VE (1992) Mol Aspects Med 13:379CrossRefGoogle Scholar
  34. 34.
    Hipkiss AR (2009) Adv Food Nutr Res 57:87CrossRefGoogle Scholar
  35. 35.
    Hipkiss AR, Worthington VC, Himsworth DTJ, Herwig W (1998) Biochim Biophys Acta 1380:46CrossRefGoogle Scholar
  36. 36.
    Pattison DI, Davies MJ (2006) Biochemistry 45:8152CrossRefGoogle Scholar
  37. 37.
    Karton A, O’Reilly RJ, Pattison DI, Davies MJ, Radom L (2012) J Am Chem Soc 134:19240CrossRefGoogle Scholar
  38. 38.
    Lee C, Yang W, Parr RG (1988) Phys Rev B 37:785CrossRefGoogle Scholar
  39. 39.
    Becke AD (1993) J Chem Phys 98:5648CrossRefGoogle Scholar
  40. 40.
    Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) J Phys Chem 98:11623CrossRefGoogle Scholar
  41. 41.
    Grimme S, Ehrlich S, Goerigk L (2011) J Comput Chem 32:1456CrossRefGoogle Scholar
  42. 42.
    Grimme S, Antony J, Ehrlich S, Krieg H (2010) J Chem Phys 132:154104CrossRefGoogle Scholar
  43. 43.
    Grimme S (2011) WIREs Comput Mol Sci 1:211CrossRefGoogle Scholar
  44. 44.
    Becke AD, Johnson ER (2005) J Chem Phys 123:154101CrossRefGoogle Scholar
  45. 45.
    Marenich AV, Cramer CJ, Truhlar DG (2009) J Phys Chem B 113:6378CrossRefGoogle Scholar
  46. 46.
    Gonzalez C, Schlegel HB (1989) J Chem Phys 90:2154CrossRefGoogle Scholar
  47. 47.
    Gonzalez C, Schlegel HB (1990) J Phys Chem 94:5523CrossRefGoogle Scholar
  48. 48.
    Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR (2012) J Cheminform 4:17CrossRefGoogle Scholar
  49. 49.
    Curtiss LA, Redfern PC, Raghavachari K (2007) J Chem Phys 127:124105CrossRefGoogle Scholar
  50. 50.
    Curtiss LA, Redfern PC, Raghavachari K (2011) Wiley Interdiscip Rev Comput Mol Sci 1:810CrossRefGoogle Scholar
  51. 51.
    Karton A (2016) Wiley Interdiscip Rev Comput Mol Sci 6:292CrossRefGoogle Scholar
  52. 52.
    Curtiss LA, Redfern PC, Raghavachari K (2005) J Chem Phys 123:124107CrossRefGoogle Scholar
  53. 53.
    Curtiss LA, Redfern PC, Raghavachari K (2010) Chem Phys Lett 499:168CrossRefGoogle Scholar
  54. 54.
    Karton A, O’Reilly RJ, Radom L (2012) J Phys Chem A 116:4211CrossRefGoogle Scholar
  55. 55.
    Karton A, Goerigk L (2015) J Comput Chem 36:622CrossRefGoogle Scholar
  56. 56.
    Yu L-J, Sarrami F, O’Reilly RJ, Karton A (2015) Chem Phys 458:1CrossRefGoogle Scholar
  57. 57.
    Cossi M, Rega N, Scalmani G, Barone V (2003) J Comput Chem 24:669CrossRefGoogle Scholar
  58. 58.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA et al (2009) Gaussian 09, Revision E.01, Gaussian Inc., Wallingford, CTGoogle Scholar
  59. 59.
    Cioslowski J (1989) J Am Chem Soc 111:8333CrossRefGoogle Scholar
  60. 60.
    De Proft F, Martin JML., Geerlings P (1996) Chem Phys Lett 250:393CrossRefGoogle Scholar
  61. 61.
    Diez RP, Baran EJ (2003) J Mol Struct 621:245CrossRefGoogle Scholar
  62. 62.
    Hansch C, Leo A, Taft RW (1991) Chem Rev 91:165CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.School of Molecular SciencesThe University of Western AustraliaPerthAustralia

Personalised recommendations