Molecular modeling of the interaction of iodinated Hoechst analogs with DNA: implications for new radiopharmaceutical design

Abstract Molecular modeling and energy minimization calculations were performed to investigate the interaction of iodoHoechst 33342 analogs with DNA. The Lamarckian genetic algorithm (AutoDock 3.0) was used to model the interaction/binding between m-iodo-p-methoxyHoechst (IMH), a ligand available in the Protein Data Bank whose binding to the minor groove of DNA has been demonstrated (crystal structure), and the oligonucleotide d(CGCGAATTCGCG)2. Since the predicted complex compared well with the crystal structure, m-iodo-p-ethoxyHoechst (IEH), a radioligand we had previously synthesized and characterized, was then docked onto DNA, the IEH–DNA complex minimized, and the binding free energy and inhibition constant (Ki) estimated and compared with those for IMH–DNA. Using the protocol, several novel iodoHoechst analogs were designed. Finally, Insight II was used to measure the distances between the iodine atom of these Hoechst analogs and the central axis of the targeted DNA, and these values were correlated with the expected (Monte Carlo calculations) and measured (experimental data) double-strand-break yield following 125I decay. The approach is general and can be applied to the interaction of diagnostic and therapeutic radiopharmaceuticals with DNA and other macromolecular targets.

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