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Title: Investigating reversible drug-DNA interactions in the major groove
Author: Crow, S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2001
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In this work a newly developed application of the PCR has been employed in conjunction with footprinting techniques to probe the molecular determinants of the drug-DNA recognition process. Hitherto this methodology has been mainly used to study minor groove association; here it has been adapted to study the major groove instead. 1. A critical review of the literature suggested the 5-methyl group of thymine and the N7 of guanine as possible determinants in major groove recognition. Novel nucleoside triphosphates were obtained that contained specific alterations at these positions. Some were known substrates for the PCR, but others were not. The suitability of the unknown compounds for utilisation in the PCR was tested by primer extension experiments. 2. Utilisation of novel nucleoside triphosphates in the PCR allowed the synthesis of unnatural DNA molecules in which characteristics of the major groove were altered significantly. It proved possible to delete, duplicate or shift the position of the 5-methyl group of thymine, or to alter its effective van der Waals size via halo-substitutions. Similarly the hydrogen bond accepting properties at the N7 of guanine were modulated. 3. Drugs known (or suspected) to associate with the major groove were subjected to footprinting experiments with these novel DNA molecules. The results were used to draw conclusions about the relative influence of the various types of base candidates in determining drug binding. It was demonstrated that both the 5-methyl group of thymine and the N7 of guanine can act as important, sometimes critical, determinants of recognition. However, particular modifications affected the binding of different drugs in different ways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available