Casey-Green, Katherine (2011) A chemical genomics approach to human drug target discovery : with test of principle using Simvastatin. PhD thesis, University of Warwick.

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Abstract

Understanding drug-protein interactions and downstream effects of these interactions underpins much of clinical pharmacology. By studying the protein targets of a small molecule we can learn about the action of this compound in the body, and this information can lead to greater understanding of mechanisms and clinical effects. We probed the polypeptide interactions of five small molecules using a human vascular phage display library, with the intention to elucidate previously unknown protein targets for the small molecule in human vasculature. A method for studying the chemical nature of this interaction was also developed. The photochemical immobilisation system used - Magic Tag® - was developed as a means of immobilising small molecules without concealing any facet of the molecule from the interaction study. Five different photochemistries are displayed in a multi-well format, to maximise diversity in the display of the small molecule. A human vascular tissue T7Select® bacteriophage display library was prepared from internal mammary artery tissues donated from patients undergoing coronary artery bypass surgery. Biopanning of the immobilised small molecule against this library allowed hypothesis generating analysis of small molecule-polypeptide interactions. Because of the non-selective nature of the photochemical immobilisation of the small molecule, several regioisomers might be expected to form on the Magic Tag® surface. To be able to connect a protein interaction with a specific face of the small molecule, analysis of this regio-non-specific interaction must be undertaken. For this purpose a cleavable resin analogue of the Magic Tag® surface was prepared.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Clinical pharmacology, Proteins, Drug targeting
Date:	January 2011
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Marsh, Andrew ; Taylor, Paul C. ; Dilly, Susan A. ; Singer, Donald R. J.
Extent:	x, 215, [61] leaves : ill., charts
Language:	eng
URI:	http://wrap.warwick.ac.uk/id/eprint/38107

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