Potent xanthine oxidoreductase inhibitors are needed to combat the recent increase in gout rates. The aim of this secondment was to use high-throughput methodology to rapidly design, synthesise and evaluate a range of potential drug candidates based on imidazole and triazole derivatives. These derivatives are of mutual interest for the applicants since they fit well into the fragment set of Sareum Ltd and they inform the development of luminescent probes for the enzyme on the academic side. By choosing a metalloenzyme as the drug target, we are taking advantage of the complementary expertise provided by the applicants: bioinorganic chemistry (AKDK) and structure-based drug discovery (Sareum).
Potent inhibitors of the enzyme xanthine oxidase are needed urgently in order to combat the recent increase in gout. The aim of this secondment was to use high-throughput methodology to rapidly design, synthesise and evaluate a range of potential inhibitors. These inhibitor molecules were of mutual interest for the applicants since they fit well into the selection of drug candidates of the industrial company and they help the development of luminescent probes for the enzyme on the academic side. By choosing an enzyme that contains a metal in the active site as target, we are taking advantage of the complementary expertise provided by the applicants: bioinorganic chemistry (AKDK) and structure-based drug discovery (Sareum).
This secondment allowed the PI to work with Sareum Ltd for 12 months in order to gain insight into the high-throughput technology that is used in industrial structure-based drug discovery. The secondment was based around a research project, which targeted the development of novel xanthine oxidase inhibitors. Three generations of potential inhibitors were synthesised and characterised. In addition, Sareum's template library was screened for alternative structures and several promising compounds were identified. A fluorimetric activity assay was developed and the compounds were tested by using high-throughput methodology, resulting in several hits with very promising inhibitory activity. In order to obtain X-ray quality crystals of the enzyme in complex with these inhibitors, an improved isolation and purification procedure for xanthine oxidase from bovine milk was developed and the crystallisation conditions for the native enzyme as well as several enzyme-inhibitor complexes were established
Acronym | XO inhibitors |
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Status | Finished |
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Effective start/end date | 1/03/06 → 28/02/07 |
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