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Title: Application of fragment-based approaches to the discovery of novel inhibitors against Mycobacterium tuberculosis pantothenate synthetase
Author: Hung, W.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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The thesis is sub-divided into four parts. The first section describes the genesis of a fragment library and the use of different biophysical techniques to identify fragments against M. tuberculosis pantothenate synthetase. Seven fragments were identified and characterized. These fragments (KD = 0.5 mM – 2.0 mM) were found to bind at three distinct sites in pantothenate synthetase, allowing for application of fragment growing and fragment linking. The second part of the thesis describes a fragment growing approach with 5-methoxyindole (KD = 1.1 mM), a fragment which was found to be binding at the active site of pantothenate synthetase. X-ray crystallography and isothermal titration calorimetry were used to guide systematic and iterative chemical elaboration of the fragment. The frequent determinations of structure and ligand efficiencies to inform decision-making during the chemical optimization process have generated a series of potent compounds. The most potent compound has a KD = 1.5 μM against M. tuberculosis pantothenate synthetase. The third part of the thesis involves the application of fragment linking with 5-methoxyindole (KD = 1.1 mM) and benzofuran-2-carboxylic acid (KD = 1.0 mM) fragments. Four different linkers were synthesized and the linked compounds were tested for binding against pantothenate synthetase. The compounds were found to bind with KD ranging 900 nM – 75 μM. X-ray crystallography of the four compounds bound to pantothenate synthetase show physical linkage of the fragments, indicating success in the fragment linking design. A comparison was made between fragment growing and fragment linking. The final part of the thesis involves optimization of the most potent compound derived from fragment growing. This employed the use of the concept of group efficiency and with further chemical modifications yielded sub-micromolar compounds against pantothenate synthetase.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available