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


Karton, A and O'Reilly, RJ and Pattison, DI and Davies, MJ and Radom, L, Computational design of effective, bioinspired HOCl antioxidants: The role of intramolecular Cl+ and H+ shifts, Journal of the American Chemical Society, 134, (46) pp. 19240-19245. ISSN 0002-7863 (2012) [Refereed Article]

Copyright Statement

Copyright 2012 American Chemical Society

DOI: doi:10.1021/ja309273n


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.

Item Details

Item Type:Refereed Article
Research Division:Chemical Sciences
Research Group:Medicinal and biomolecular chemistry
Research Field:Biomolecular modelling and design
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the chemical sciences
UTAS Author:O'Reilly, RJ (Dr Robert O'Reilly)
ID Code:84971
Year Published:2012
Web of Science® Times Cited:18
Deposited By:Chemistry
Deposited On:2013-06-07
Last Modified:2013-07-02

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