The purpose of this project is to use computational drug design, medicinal chemistry, and biological assays, to identify new potential antiinfective drug leads. The position will suit students with a strong interest and background in synthesis who would also like to develop skills in computational molecular design and molecular and cellular biology. You will work in a vibrant, multidisciplinary research group consisting of medicinal chemists and molecular/cell biologists.
Infections derived from parasitic organisms are a major cause of mortality throughout the world. For example, 50% of the world’s population is at risk of infection from the parasites which cause malaria. Resistance to all current chemotherapeutics used in the treatment of this illness has been observed and there is therefore, an urgent requirement for the development of novel chemotherapeutics to combat this disease, particularly against strains which have developed resistance to earlier therapies. Additionally, diseases from other parasites such as toxoplasmosis are on the increase. Dihydroorotate dehydrogenase (DHODH), the enzyme which catalyses the fourth step in de novo biosynthesis of pyrimidines, has been shown to be an effective target for the development of novel chemotherapeutics. No drugs currently used in the treatment of parasitic diseases (such as malaria) target this enzyme however, and therefore there is no previously observed resistance. Our group has pioneered the application of computational structure-based drug design methods to this enzyme resulting in the development of novel and highly potent inhibitor series.
This project will build upon our knowledge of the DHODH enzyme to develop highly potent and selective DHODH inhibitors to combat the threats posed by a range of pathogenic organisms including those that cause malaria, toxoplasmosis, and bacterial infections.
The project will allow you to develop expertise and skills in a number of key areas linked to synthetic organic and medicinal chemistry including advanced aspects of structure-based molecular design, efficient synthesis of compound libraries to enable biological screening, the use of efficient assay methods to establish biological activity of inhibitors, and the use of ADMET data to improve drug likeness.
Paul T. P. Bedingfield, Deborah Cowen, Paul Acklam, Fraser Cunningham, Mark R. Parsons, Glenn A. McConkey, Colin, W. G. Fishwick, A. Peter Johnson. The Role of Inhibitor-Induced Structural Changes in the Selective Inhibition of Human- and Plasmodium Dihydroorotate Dehydrogenase. J. Med. Chem., 2012, 55, 5841–5850; Katie J. Simmons, Ian Chopra, and Colin W.G. Fishwick Structure-based discovery of antibacterial drugs. Nature Reviews Microbiology, 2010, 8, 501-510; Cunningham, F., McPhillie, MJ., Johnson, AP., Fishwick, CW. An in silico structure-based design approach to anti-infective drug discovery. Parasitology, 2014, 141, 17 – 27.