Computational design of effective, bioinspired HOCl antioxidants: The role of intramolecular Cl+ and H+ shifts

Amir Karton, Robert J. O'Reilly, David I. Pattison, Michael J. Davies, Leo Radom

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

The enzyme myeloperoxidase generates significant amounts of hypochlorous acid (HOCl) at sites of inflammation to inflict oxidative damage upon invading pathogens. However, excessive production of this potent oxidant is associated with numerous inflammatory diseases. Recent kinetic measurements suggest that the endogenous antioxidant carnosine is an effective HOCl scavenger. On the basis of computational modeling, we suggest a possible mechanism for this antioxidant activity. We find that a unique structural relationship between three adjacent functional groups (imidazole, carboxylic acid, and terminal amine) enables an intramolecular chlorine transfer to occur. In particular, two sequential proton shifts are coupled with a Cl+ shift converting the kinetically favored product (chlorinated at the imidazole nitrogen) into the thermodynamically favored product (chlorinated at the terminal amine) effectively trapping the chlorine. We proceed to design systems that share similar structural features to those of carnosine but with even greater HOCl-scavenging capabilities.

Original languageEnglish
Pages (from-to)19240-19245
Number of pages6
JournalJournal of the American Chemical Society
Volume134
Issue number46
DOIs
Publication statusPublished - Nov 21 2012

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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