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Durham e-Theses
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Crystallographic Studies for Structure-Based Drug Design

TATUM, NATALIE,JOAN (2012) Crystallographic Studies for Structure-Based Drug Design. Masters thesis, Durham University.

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Structure-based drug design is an iterative design cycle reliant upon lead fragments and a known target. The result is two separate avenues of structure-based drug design, explored in this thesis: speculative, with no defined target (in the form of peptoid precursors) and rational, with a characterized target (in the form of EthR inhibitors).

Peptoids are N-substituted glycine molecules, able to mimic peptide structure and function with notable advantages for drug delivery and independent function. Here, the structures of two precursor molecules are presented as part of a wider aim to produce a tool-box of peptoid monomers for a fragment-based approach. The intramolecular interactions made by the two precursors can be extrapolated for the final peptoid.

EthR is a transcriptional repressor from Mycobacterium tuberculosis, a part of the activation pathway for the second-line drug ethionamide. It has been shown that inhibition of EthR results in a conformational change which renders the protein inactive, resulting in an increase in the bioactivation of ethionamide and so increased drug efficiency. Inhibitors for EthR have been designed, able to effect this response in vitro and in vivo.

This thesis details the crystallisation and structural study of peptoid precursors for use as lead fragments or monomers for peptoid click chemistry; and EthR inhibitors for improving the bioactivation and efficacy of ethionamide, with evaluation by molecular docking analysis in AutoDock Vina. The results show that shorter ligands, capable of engaging certain residues in the ligand-binding channel, are rated highest and so indicated to be the more effective inhibitors.

The two approaches highlight the diversity of tactics for new therapeutics and the powerful advantage of three-dimensional crystal structures, acquired through X-ray crystallography, to the drug design process.

Item Type:Thesis (Masters)
Award:Master of Science
Keywords:drug design, crystallography, peptoids, transcriptional repressors, inhibitors, x-ray crystallography, structure-based drug design
Faculty and Department:Faculty of Science > Biological and Biomedical Sciences, School of
Thesis Date:2012
Copyright:Copyright of this thesis is held by the author
Deposited On:31 May 2012 09:55

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