Evaluation of DNA intercalation potential of pharmaceuticals and other chemicals by cell‐based and three‐dimensional computational approaches

To what extent noncovalent chemical‐DNA interactions, in particular weak nonbonded DNA intercalation, contribute to genotoxic responses in mammalian cells has not been fully elucidated. Moreover, with the exception of predominantly flat, multiple‐fused‐ring structures, our ability to predict intercalation ability of novel compounds is nearly completely lacking. Computational programs such as DEREK and MCASE recognize primarily those molecules that can form irreversible covalent adducts with DNA since their learning sets, for the most part, have not been populated by compounds for which a relationship between noncovalent interaction and genotoxicity exists. We describe here a novel three‐dimensional (3D) computational DNA‐docking model for prediction of DNA intercalative activity of molecules with both classical and nonclassical intercalating structures. The 3D docking results show a remarkable concordance with results obtained from testing these molecules directly in the Chinese hamster V79 cell‐based bleomycin amplification system suggesting that either or both of these approaches may have utility in defining noncovalent chemical‐DNA interactions. The ability to predict and/or demonstrate cellular DNA intercalation of novel molecules may well provide fresh insights into the nature and mechanistic basis of structurally unexpected genotoxicity observed during safety testing. Environ. Mol. Mutagen. 44:163–173, 2004. © 2004 Wiley‐Liss, Inc.