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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043129-02
Application #
3302076
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1989-12-01
Project End
1992-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Geierstanger, B H; Mrksich, M; Dervan, P B et al. (1994) Design of a G.C-specific DNA minor groove-binding peptide. Science 266:646-50

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