Molecular simulation of ligand-binding with DNA: implications for 125I-labeled pharmaceutical design

By using computer-assisted molecular modeling software, to assess the effects of structural modification on the interaction of 125I-labeled iodoHoechst ligands and DNA and to design new analogs with specified distances between the Auger-electron-emitting 125I atom and the DNA central axis.

The Lamarckian genetic algorithm (AutoDock 3.0) was used to model the interaction between DNA and m-iodo-p-methoxyHoechst (IMH), a ligand whose binding to the minor groove of DNA has been demonstrated (crystal structure) and which is available in the Protein Data Bank. 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 (IH-A and IH-B) were designed. Finally, Insight II was used to measure the distances between the iodine atom (e.g. 125I) of these Hoechst analogs and of 5-iodo-2'-deoxyuridine (IdUrd) and the central axis of the targeted DNA, and these values were correlated with the expected/measured DSB yield following 125I decay.

The docking of IMH and DNA leads to a ligand-DNA complex approximately 1 A RMSD (root mean square deviation) from the crystal-structure position, and the IEH-DNA complex also has a small RMSD (1.27 A). The distances between the 125I atom and the DNA central axis are estimated as 8.61 A for IMH, 9.20 A for IEH and 5.7A for IdUrd. For the newly designed analogs, the distances from the 125I atom to the central DNA axis are 10.92 A for IH-A and 16.39 A for IH-B.

These software programs can predict the reactivity of newly designed radiolabelled molecules with their targeted DNA molecules by molecular modeling prior to their chemical synthesis.