Drug—DNA Interactions

  • David E. Graves
Part of the Methods in Molecular Biology™ book series (MIMB, volume 95)


The interactions of small molecules with nucleic acids have provoked considerable interest in the field of antitumor drug design over the past three decades; however, critical information linking the physical-chemical properties associated with these complexes with their biological effectiveness remains unclear. Significant progress has been made toward unraveling the structural and dynamic properties of many ligand-DNA complexes, which has provided pivotal insight into the design and development of more effective secondgeneration chemotherapeutic agents for the successful treatments of many types of cancer (see ref. 1 and references therein). Over a decade ago, a primary cellular target for many of these agents was identified to be topoisomerase II through formation of a ternary complex among the ligand, DNA, and enzyme (see reviews in refs. 2, 3, 4, 5). Interestingly, DNA binding affinity did not directly correlate with antitumor activity; however, modulation of topoisomerase II activity was shown to coincide with biological activity of these agents (6). Interactions of ligands with DNA are being explored using a variety of physical and biochemical methods in an effort to determine the chemical and physical basis of novel binding phenomena, such as DNA base sequence selectivity, correlation of structure-activity relationships dictating the geometry and thermodynamics of drug-DNA complexes, the influences of substituent modifications on the drug-DNA complex, and the correlation between these chemical and physical properties with the compounds’ effectiveness in eliciting topoisomerase II inhibition. The methods described herein provide several basic approaches used in examining drug-DNA interactions.


Binding Constant Equilibrium Dialysis Free Drug Concentration Binding Isotherm Total Drug Concentration 
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© Humana Press Inc. 2001

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  • David E. Graves

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