Computational antioxidant design

Using supercomputers to design potent bioinspired antioxidants

Oxidative damage to DNA and proteins is a major cause of many chronic inflammatory diseases including cancer, arthritis and cardiovascular disease. In recent work, we elucidated the molecular mechanism by which the potent endogenous antioxidant carnosine operates.

We showed that a unique structural relationship between three adjacent functional groups (imidazole, carboxylic acid and terminal amine) enables carnosine to work via a novel two-step mechanism. Initial chlorination occurs at the imidazole nitrogen (the kinetically favoured site), followed by an intramolecular chlorine atom (Cl) transfer in which the Cl is transferred to the terminal primary amino nitrogen (the thermodynamically favoured site) effectively trapping the chlorine. This bifunctional mechanism is illustrated schematically in Figure 2. Based on this discovery of carnosine’s two-step mechanism, we designed improved bifunctional antioxidants against oxidative damage mediated by hypochlorous acid (HOCl). The bio-inspired antioxidants trap the noxious chlorine atom at rates several orders of magnitude faster than carnosine.

This work was featured in the Research Highlights section of Nature Chemistry and opens the way for further computational design of potent bifunctional antioxidants that selectively target strong oxidising agents.

The aim of this PhD project is to provide an innovative basis for the development of new antioxidants to alleviate or circumvent the damage resulting from HOCl-induced oxidative stress.

The project will decipher the reaction mechanisms by which HOCl oxidises biologically important purine bases (e.g. guanine, cytosine, thymine, uracil), and other biomolecules incorporating nitrogen-heterocycle functionalities (for example substituted imidazole, pyrazole, diazines, naphthyridine).

These biomolecules are ideal candidates to serve as “kinetic traps” in bifunctional antioxidants; e.g. carnosine uses an imidazole ring as the kinetically preferred site (Figure 2). These heterocycles have multiple multiple nitrogen-hydrogen bonds that are prone to oxidation.

The project will address questions such as:

  • Which sites are kinetically favoured and which are thermodynamically favoured?
  • Can we control the outcome by changing the reaction conditions (temperature, solvent, etc.)?
  • What are the rate-determining steps?

These discoveries will allow us to design novel bio-inspired antioxidants that specifically target the HOCl-mediated oxidative stress occurring in many chronic diseases.

Figure 1


Figure 2

Suggested readings

Karton, R. J. O’Reilly, D. I. Pattison, M. J. Davies and  L. Radom, Computational design of effective, bio-inspired HOCl antioxidants: the role of intramolecular Cl+ and H+ shifts. Journal of the American Chemical Society, 134, 19240–19245 (2012). 

F. Sarrami, L.-J. Yu, and A. Karton. Computational design of carnosine-based HOBr antioxidants. Journal of Computer-Aided Molecular Design, 31, 905–913 (2017). 

Research Assistant Professor Amir Karton

I am the head of the computational chemistry group at the School of Molecular Sciences. I currently hold an ARC Discovery Early Career Researcher Award fellowship. My main research interests lie in the development of quantum chemical theory and the application of these theories to solving problems of chemical structure, mechanism and molecular design.

How to apply

Interested in becoming part of this project? Complete the following steps to submit your expression of interest:

Step 1 - Check criteria

General UWA PhD entrance requirements can be found on the Future Students website.

  • We are looking for highly motivated students who are interested in the area of theoretical chemistry
  • A background in organic and/or biological chemistry is an advantage
  • Background in programing (e.g. C, Perl, or Fortran) and a UNIX environment is an advantage (but not essential)

Step 2 - Submit enquiry to research team leader

Step 3 - Lodge application

After you have discussed your project with the research team leader, you should be in a position to proceed to the next step of the UWA application process: Lodge an application. Different application procedures apply to domestic and international students.


Scholarships specific to this project

A top-up scholarship of AUD$5000 per annum (3 years) is available for a PhD candidate who is successful in obtaining a scholarship to investigate this important topic. One-off relocation expenses from overseas up to AUD$2500 will be reimbursed.

International students should consider Endeavour Award scholarships and Australia Awards Scholarships.

Domestic students

All domestic students may apply for Research Training Program and University Postgraduate Awards (UPA) scholarships.

The Australian Government's Endeavour Awards and Scholarships are available to Australian applicants for study in participating countries and regions.

International students

A range of scholarships are available from international organisations and governments. The full list, organised by country, is available on the Future Students website.

In addition, all international students may apply for International Research Training Program scholarships.

The Australian Government's Endeavour Awards and Scholarships are available to international applicants from participating countries and regions.

Indigenous students
Indigenous students are encouraged to apply for Indigenous Postgraduate Research Supplementary Scholarships.
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