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

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

SN - 0002-7863

VL - 134

SP - 19240

EP - 19245

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 46

ER -