Molecular modeling of DNA with minor groove binding agents and intercalators

The molecular modeling of several drugs in complexes with deoxyribonucleic acid (DNA) was undet1aken. Selected bis-lexitropsins, based upon NMR and modeling studies of bis-distamycin A, were modeled with an oligonucleotide d(CGAACA TGTTCG)2 using MidasPlus and AMBER 4.0. Intercalators ethidium, ellipticinc. mitoxantrone, and bisantrene were modeled with an oligonucleotide d(CGCG)~ using SpartanPlus and DOCK 4.0. The binding site was prepared from an x-ray study of this oligonucleotide interacting with ditercalinium, a bis-intercalator. The purpost: of this study was to estimate the conformation and orientation of the molecules in tht:ir rt:spcctive binding sites. The mndding study of the bis-lexitropsins showed good agreement with previous modeling studies on distamycin and would be further enhanced by acquisition and interpretation ofNOESY NMR data. The computer modeling study shows that one of the bis-lexitropsins (pyrrole-pyrrole-imidazole, PPI) forms several hydrogen bonds between subunits, which may make it less effective for binding DNA. The other bis-lexitropsin (pyrrole-imidazole-pyrrole, PIP) also forms some interactions between dimers, but is mainly occupied with binding to the DNA and therefore has a more favorable interaction energy for binding to the chosen sequence. The intercalators were similarly agreeable with previous models. Bisantrene has the most favorable interaction energy. It threads its sidechain through the DNA so that while the planar aromatic ring system stacks between base pairs, there is one sidechain in the major groove and one in the minor groove. These extra interactions between the drug and DNA help the interaction to be more favorable