The goal of this project is to improve our understanding of drugs which bind in the minor groove of DNA, with a preference for specific sequences. There are a considerable variety of these which have been prepared, almost all of which prefer binding at A-T rich regions of DNA. At present the basis for this sequence preference is not well understood, hampering further design of new molecules with improved binding specificity. The work which will be done will use primarily NMR spectroscopy to identify specific binding sites for a variety of drugs on DNA oligomers. These will include many sequence variants containing both normal base pairs, A-T and G-C, and also inosine-cytosine pairs, which do not occur naturally. The comparison of binding modes will help our understanding of specific functional groups which are required for identified and will be investigated, which should help in understanding structural features which lead to preferential binding. Possibilities of exploiting this cooperative binding mode in new drugs will be explored. The mechanisms of transfer of drug molecules between the available binding sites will also be determined. NMR spectroscopy provides a method for simultaneous determination of many different transfer rates. Alterations in structures of known drugs will be made to determine the effects on binding site specificity and exchange kinetics.
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