Toward a greater appreciation of noncovalent chemical/DNA interactions: application of biological and computational approaches.
Noncovalent DNA interactions, e.g., DNA intercalation and DNA groove-binding, have not been well studied relative to covalent interactions largely due to the inability of predicting and detecting such events in intact cells. We have adapted an in vitro bleomycin amplification method for DNA intercalation for use in cultured V79 Chinese hamster cells and have validated this approach through the use of a three-dimensional DNA computational docking model that quantifies potential strength of DNA intercalative binding based on electrostatics and hydrogen bonding. For many structural classes of molecules, DNA intercalation is necessary but not sufficient for genotoxicity. The present article reviews our progress to date in predicting and confirming noncovalent binding of drugs and other chemicals and in understanding the mechanistic relationship between intercalation and genotoxicity.
Snyder
Ronald D
RD
Schering-Plough Research Institute, Lafayette, New Jersey 07848, USA. ronald.snyder@spcorp.com
Hendry
Lawrence B
LB
D000818:Animals; D016466:CHO Cells; D019295:Computational Biology / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity
D007364:Intercalating Agents; D009153:Mutagens; D004247:DNA