Project Details

Description

Our long-term goal is to develop an understanding of the molecular forces
that dictate and control the affinity and specificity of drug binding to
DNA. Such a molecular understanding of drug-DNA interactions is a
prerequisite for the development of a rational basis for drug design. Our
approach is to determine complete thermodynamic binding profiles for the
complexation of several antitumor and antiviral drugs to various DNA host
duplexes. Specifically, spectroscopy and batch calorimetry will be
employed to characterize thermodynamically the binding event as a function
of the structure of the drug and the sequence of both oligomeric and
polymeric host DNA's. These thermodynamic binding profiles for each drug
will allow us to: define the nature of the forces that drive complexation
and predict the temperature-dependent stability of the complex; determine
the thermodynamic origin of sequence binding preferences; define the
thermodynamic basis for cooperative binding; evaluate the role of specific
structural features of the drug by comparing the binding data on a series
of drug analogues; correlate the thermodynamic data with the mode of
binding and the molecular picture of the complex; resolve drug-induced
conformational changes from local, specific drug-DNA interactions by
comparing binding data on corresponding oligomeric and polymeric DNA hosts;
evaluate the thermodynamic basis for drug synergism by comparing binding
data for a drug in the presence and absence of other drugs. Differential
scanning calorimetry will be used to detect, monitor, and thermodynamically
characterize the influence of drug binding on the melting behavior of the
host duplex. In particular, the size of the cooperative melting unit for
each host duplex will be determined in the presence and absence of each
drug. This parameter will provide a measure of the influence of drug
binding and base sequence on the ability of a polymer chain to propagate
molecular distortions -- a property which undoubtedly is of great
importance in numerous biological processes. Calorimetry represents the
only experimental method by which the relevant thermodynamic data can be
obtained in a direct and model-independent manner. In conjunction with
standard spectroscopic techniques, this proposal is designed to exploit the
unique powers of batch and differential scanning calorimetry to obtain
complete thermodynamic and extra-thermodynamic profiles of the solution
properties of drug binding and the resultant drug-DNA complexes.Description
StatusFinished
Effective start/end date1/1/8512/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $184,703.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.