Sustain approach to Biomedical Sci CDT

Catalysis by metal-ion dependent enzymes plays key role in a myriad of biological processes. Many metallo-enzymes are validated or potential drug targets and they also play key roles in drug, in particular antibiotic, resistance. The overwhelming malprity of metallo-enzyme inhibitors are simple, active site blocking compounds, that normally complex to the catalytically important metal ion. There are, however, exceptions, perhaps, most notably aspirin, which inhibits its target cyclooxygenase enzyme by acylating an active site proximate residues, so reducing enzyme catalysis. Aspirin, however, was discovered by empirical in-vivo testing and would be very unlikely to be discovered by contemporary methods, including existing structural and computational ones. This project aims to use structural and mechanistic knowledge, coupled with advanced computational methods to identify new aspirin-inspired ways of inhibiting metallo-enzymes, focussing on key enzymes involved in resistance to antibiotics. Working with the Ineos Oxford Institute this project falls under the EPSRC Chemical Biology and antimicrobial resistance research areas.