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 basis for their different selectivity against topo I and II and varying potency, the binding of six compounds to d(CGTACG) was studied by molecular modeling. Modeling data were in good agreement with physical data showing that five compounds intercalated DNA with the anthraquinone chromophore orientated in parallel to the long dimension of the d(CpG) base pairs and the amino acid placed in the minor groove. Differences in binding modes emerged which correlated to different biological properties. 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, arginine and NU/ ICRF 512, methionine) were inserted into the minor groove, whereas the C-terminal groups (hydrazide) of two potent topo II inhibitors (NU/ICRF 500 and 506, serine) were placed into the minor groove while the amino acid side chains pointed away from the minor groove. These data provide structural information which may prove valuable in rational design of second generation analogs.