The development of anticancer drugs started over four decades ago, with the serendipitous discovery of the antitumor activity of cisplatin and its successful use in the treatment of various cancer types. Despite the efforts made in unraveling the mechanism of the action of cisplatin, as well as in the rational design of new anticancer compounds, in many cases detailed structural and mechanistic information is still lacking.

Many of these drugs exert their anticancer activity by covalently binding to DNA inducing a distortion or simply impeding replication, thus triggering a cellular response, which eventually leads to cell death. A detailed understanding of the structural and electronic properties of drug–DNA complexes and their mechanism of binding is the key step in elucidating the principles of their anticancer activity. At the theoretical level, the description of covalent drug–DNA complexes requires the use of state-of-the-art computer simulation techniques such as hybrid quantum/classical molecular dynamics simulations.

In this review we provide a general overview on: drugs which covalently bind to DNA duplexes, the basic concepts of quantum mechanics/molecular mechanics (QM/MM), molecular dynamics methods and a list of selected applications of these simulations to the study of drug–DNA adducts. Finally, the potential and the limitations of this approach to the study of such systems are critically evaluated.