Computational design of bio-inspired carnosine-based HOBr antioxidants
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%.
KeywordsMolecular design Antioxidant design Computational chemistry CCSD(T) G4(MP2) theory
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.
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