Naphthyridinomycin-DNA adducts: a molecular modeling study.

Monocovalent groove binding complexes of antitumor antibiotic naphthyridinomycin and its analogs with DNA sequence d(ATGCAT)2 have been studied by molecular mechanics to understand which enantiomer of the drug and what chirality at C(7) of the drug are preferred for forming better drug-DNA adducts. The effect of hydroquinone intermediate and the substitution at C(11) on drug-DNA interactions have also been investigated. The results indicate that the enantiomer that forms the best adduct is different from the one reported earlier in the literature. The drug with an R configuration at C(7) is preferred for binding. The hydroquinone models do not necessarily provide a given analog of the drug with additional favorable DNA interactions. The substitution at C(11) by OH provides the best binding model. This finding agrees well with the results from previous biochemical studies. The sequence specific studies indicate that the sequence d(ATGCAT)2 is slightly preferred over others.