Drug-nucleic Acid Interactions

Preface Progress in molecular biology and studies of small molecule binding to nucleic acids have been inextricably linked. A testament to that fact is the inclusion of eight papers directly concerned with drug-DNA interactions among the recently published list of the 100 most cited articles in the Journal of Molecular Biology. Few other scientific areas are as well represented on that list. Small molecules have perhaps taught us more about DNA than DNA has taught us about small molecules. Watson, for example, notes in the Molecular Biology of the Gene that the "fact that intercalation occurs so readily indicates that it is energetically favored... [and] is additional evidence for the metastability of the double-helical structure--its ability to assume many inherently unstable configurations that normally revert quickly back to the standard B conformation." From that point of view, intercalation provided one of the very first indications of the plasticity of DNA, an area that has blossomed to reveal an incredible diversity of structural forms. Perhaps the most widespread interest in small molecules that bind to nucleic acids stems from their potential as useful pharmaceutical agents. Indeed, some of the very best anticancer drugs are well-documented DNA binders. While interest in drug-DNA interactions has at times waned, recent advances in chemical synthesis, analytical instrumentation to measure binding, and structural biology have greatly enhanced the potential for rational design of new therapeutic compounds. Accordingly, studies on the interaction of small molecules with nucleic acids have taken on new life and h