Molecular modeling of the antitumor agents azinomycins A and B: Force-field parametrization and DNA cross-linking-based filtering

We describe a molecular modeling study on the DNA cross-linking agents azinomycins A and B. Analysis of five force fields and development of a new set of parameters were performed using ab initio calculations and experimental data to evaluate properly the potential energy profile of this structurally unique class of natural products. Critical fragments were identified on the basis of their potential role in determining the conformational shape of the agents relative to the site of action on the DNA duplex. A new conformational analysis protocol was developed on the basis of a hypothetical cross-linking mechanism where the distance and topology of the reactive sites on DNA were transformed into geometrical descriptors that were used to filter minimized conformations.