Drug-DNA interactions

Abstract

Structures of drug-DNA oligomer complexes provide a molecular basis for the interpretation of sequence-selective binding as measured by DNA footprinting. Thermodynamic data, obtained from calorimetry, thermal denaturation, and equilibrium measurements are also an important aspect of drug-DNA complex formation. Although many ligand-DNA complexes exhibit a single conformation in solution, there are examples of systems undergoing exchange between two or more conformations in solution. A 2-aminofluorene-DNA oligomer duplex adopts two conformations, one exhibiting Watson-Crick pairing at the modified guanine, and a second conformation in which base pairing is disrupted and the fluorene moiety is stacked within the duplex. NMR-derived structures of oligonucleotides with actinomycin D, nogalomycin, bisintercalartors, lexitropsins and triplex binding ligands highlight recent advances in this area. The development of (pyridine-2-carboxamide-neotropsin)2-C6, a synthetic dimer that binds in the minor groove, is but one example of the synergistic interaction of NMR structural analysis, molecular modeling, and chemical synthesis.