MOLECULAR MODELING OF THE INTERACTION OF ANTHRACENYL-AMINO ACID TOPOISOMERASE INHIBITORS WITH THE DNA-SEQUENCE D(CGTACG)

Anthracenyl-amino acid and dipeptide conjugates represent new classes of topoisomerase (topo) inhibitors. To investigate the structural basi s for their different selectivity against topo I and II and varying po tency, the binding of six compounds to d(CGTACG) was studied by molecu lar modeling. Modeling data were in good agreement with physical data showing that five compounds intercalated DNA with the anthraquinone ch romophore orientated in parallel to the long dimension of the d(CpG) b ase pairs and the amino acid placed in the minor groove. Differences i n binding modes emerged which correlated to different biological prope rties. The amino acid chain of the topo I inhibitor (NU/ICRF 600, gly- phe) extended significantly out from the helical axis horizontal. The amino acid side chains of two topo II inhibitors (NU/ICRF 510, arginin e and NU/ICRF 512, methionine) were inserted into the minor groove, wh ereas the C-terminal groups (hydrazide) of two potent topo II inhibito rs (NUI/CRF 500 and 505, serine) were placed into the minor groove whi le the amino acid side chains pointed away from the minor groove. Thes e data provide structural information which may prove valuable in rati onal design of second generation analogs.