DNA cross-linking by azinomycin B: Monte Carlo simulations in the evaluation of sequence selectivity.

A new set of charges specifically developed for biologically relevant N7-alkylated purine adducts have been implemented in the AMBER force field of the MacroModel package and applied to the conformational search of azinomycin B-DNA interactions. To perform a sequence dependent reactivity relationship study, four DNA triplets known to interact differently with the drug, 5'-GCT-3', 5'-GCC-3', 5'-GTC-3', and 5'-GTT-3', have been modeled in B-form and intercalative conformations. Monte Carlo simulations of all possible monoadducts and intercalative complexes have been carried out and analyzed using a filtering criterion that estimates the probability of covalent bond formation and covalent cross-linking. We observed a good correlation between existing experimental data and our computational estimations that validate the approach. The comparison of the conformational properties of the drug-DNA monoadducts and complexes confirms the most probable mechanism of action involving an initial aziridine and subsequent epoxide alkylation. The different hydrogen bond network in the monoadducts and in the intercalative complexes between the drug and the three base-pair receptor is the primary reason for the different cross-linking reactivity. In addition, steric hindrance of the major groove exposed methyl group of central thymine-based triplets plays an important role in the lack of the reactivity of these sequences. Synthetic work on the azinomycins and the information coming from this computational study will be important for the design of more potent or DNA sequence-selective agents based on the azinomycin skeleton.