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Title: Phosphofructokinase as a target for rational drug design
Author: Rigden, Daniel
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1994
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There is a pressing need for new anti-parasitic drugs. Parasitic infection is an enormous, and growing, worldwide problem. Current treatments are generally ineffective and cause side-effects. Organisms resistant to some of the more effective drugs are appearing. A good target for drug intervention is glycolysis on which many parasites rely for their energy supply. Phosphofructokinase (PFK) is a good choice of glycolytic enzyme for targeting since it is belived to catalyse the major regulatory step of glycolysis. However, inhibition of parasite PFK must take place with as little inhibition of the host PFK as possible. The aim of this work was to tackle this problem of species selectivity. In the absence of much information about parasite PFKs, a model system was used which comprised two of the best-studied PFKs. The goal was inhibition of Escherichia coli PFK by compounds little affecting rabbit muscle PFK. Models of the structure for rabbit muscle PFK were built based on the justified assumption of a shared protein fold with Escherichia coli PFK. Several ligand design approaches were used. Some used protein structure information like the program LUDI. Database searches used information from the structures of known ligands. The question of species selectivity was addressed during the design process. Several classes of putative ligands were produced. These ranged from disparate organic componds suggested by LUDI to substrate analogs modelled using molecular mechanics procedures. Testing of putative ligands was by a variety of techniques such as enzymes assay fluorescence and protection against protein denaturation. Finally, the results were summarised and future prospects considered.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available