Atomistic‐Level Portrayal of Drug–DNA Interplay: A History of Courtships and Meetings Revealed by Molecular Simulations

Abstract Simulation techniques play an ever increasing role in drug design by providing an atomistic view of the pathways of drugs to their target sites, thus revealing the determinants behind molecular recognition and binding, pinpointing local and allosteric conformational changes of both drugs and receptors, and unveiling key chemical mechanisms in enzymatic‐like processes. In particular, molecular dynamics simulations, relying on a force field, quantum mechanical, or hybrid description of the system, have been largely employed to unveil mechanistic, kinetic, and thermodynamic aspects of the binding of anticancer drugs to DNA, ultimately contributing to a better understanding of their mechanism of action. Herein we review recent literature, focusing on selected examples from our work, to show how modern computer simulations can be applied to study the mechanism of action of antitumor drugs such as platinum compounds, organic antibiotics, and metal‐based octahedral complexes, which are archetypal examples of the most common classes of DNA binding molecules. We discuss the strengths and limitations of in silico studies in this field, as well as current and future challenges.