Model building and molecular mechanics calculations of mitoxantrone-deoxytetranucleotide complexes: Molecular foundations of DNA intercalation as cytostatic active principle

SummarySeveral intercalation complexes of the antitumor-active drug mitoxantrone with base paired tetranucleotides were constructed by molecular modeling using computer graphics and molecular mechanics calculations. The mitoxantrone molecule favours DNA binding into CG intercalation site. The two side chains of the drug are orientated into the major groove and fixed by hydrogen bonds with the nucleotide bases. This molecular study can be helpful for understanding the mode of action of cytostatically active compounds and to design new structurally related compounds of the anthraquinone drug type.ZusammenfassungVerschiedene Interkalationskomplexe aus dem antitumor-aktiven Arzneistoff Mitoxantron und basengepaarten Tetranukleotiden wurden mit Hilfe der Methoden des Molecular Modelings unter Einsatz von Computergraphik und molekülmechanischen Rechnungen konstruiert. Mitoxantron bevorzugt die Einlagerung in eine CG-Basensequenz. Beide Seitenketten des Wirkstoffs orientieren sich nach der großen Rinne und sind über Wasserstoffbrücken mit den DNA-Basen verbunden. Diese molekulare Studie soll dazu beitragen, den Wirkmechanismus zytostatisch aktiver Substanzen zu verstehen und neue strukturell verwandte Verbindungen vom Anthrachinon-Typ zu entwerfen.

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