Computational design of effective, bioinspired HOCl antioxidants: the role of intramolecular Cl+ and H+ shifts
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Computational design of effective, bioinspired HOCl antioxidants : the role of intramolecular Cl+ and H+ shifts. / Karton, Amir; O'Reilly, Robert J; Pattison, David I; Davies, Michael Jonathan; Radom, Leo.
In: Journal of the American Chemical Society, Vol. 134, No. 46, 21.11.2012, p. 19240-5.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Computational design of effective, bioinspired HOCl antioxidants
T2 - the role of intramolecular Cl+ and H+ shifts
AU - Karton, Amir
AU - O'Reilly, Robert J
AU - Pattison, David I
AU - Davies, Michael Jonathan
AU - Radom, Leo
PY - 2012/11/21
Y1 - 2012/11/21
N2 - 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.
AB - 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.
KW - Antioxidants
KW - Chlorides
KW - Drug Design
KW - Hypochlorous Acid
KW - Models, Molecular
KW - Protons
U2 - 10.1021/ja309273n
DO - 10.1021/ja309273n
M3 - Journal article
C2 - 23148773
VL - 134
SP - 19240
EP - 19245
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 46
ER -
ID: 128974565