Drug-DNA recognition: energetics and implications for design

In this article we review thermodynamic studies designed to examine the int eraction of low molecular weight ligands or drugs with DNA. Over the past 1 0 years there has been an increase in the number of rigorous biophysical st udies of DNA-drug interactions and considerable insight has been gained int o the energetics of these binding reactions. The advent of high-sensitivity calorimetric techniques has meant that the energetics of DNA-drug associat ion reactions can be probed directly and enthalpic and entropic contributio ns to the binding free energy established, There are two principal conseque nces arising from this type of work, firstly three-dimensional structures o f DNA-drug complexes from X-ray and NMR studies can be put into a thermodyn amic context and the energetics responsible for stabilizing the observed st ructures can be more fully understood. Secondly, any rational approach to s tructure-based drug design requires a fundamental base of knowledge where s tructural 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 algorithm s. In this review we describe recent breakthroughs in duplex DNA-directed d rug design and also discuss how similar principles are now being used to ta rget higher-order DNA molecules, for example, tripler (three-stranded) and tetraplex (four-stranded) structures. Copyright (C) 2000 John Wiley & Sons, Ltd.