Drug-DNA recognition: energetics and implications for design.

In this article we review thermodynamic studies designed to examine the interaction of low molecular weight ligands or drugs with DNA. Over the past 10 years there has been an increase in the number of rigorous biophysical studies of DNA-drug interactions and considerable insight has been gained into the energetics of these binding reactions. The advent of high-sensitivity calorimetric techniques has meant that the energetics of DNA-drug association reactions can be probed directly and enthalpic and entropic contributions to the binding free energy established. There are two principal consequences arising from this type of work, firstly three-dimensional structures of DNA-drug complexes from X-ray and NMR studies can be put into a thermodynamic context and the energetics responsible for stabilizing the observed structures can be more fully understood. Secondly, any rational approach to structure-based drug design requires a fundamental base of knowledge where structural detail and thermodynamic data on complex formation are intimately linked. Therefore these types of studies allow a set of general guidelines to be established, which can then be used to develop drug design algorithms. In this review we describe recent breakthroughs in duplex DNA-directed drug design and also discuss how similar principles are now being used to target higher-order DNA molecules, for example, triplex (three-stranded) and tetraplex (four-stranded) structures. Copyright 2000 John Wiley & Sons, Ltd.