Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies

• Published in: ChemMedChem 2016-06, Vol.11 (12), p.1199-1210
• Main Authors: Palermo, Giulia, Magistrato, Alessandra, Riedel, Tina, von Erlach, Thibaud, Davey, Curt A., Dyson, Paul J., Rothlisberger, Ursula
• Format: Article
• Language: English
• Subjects: antitumor agents; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - metabolism; Chromatin; Chromatin - chemistry; Chromatin - metabolism; Coordination Complexes - chemistry; Coordination Complexes - metabolism; Coordination Complexes - therapeutic use; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; drug design; Humans; medicinal chemistry; metal complexes; molecular dynamics; Molecular Dynamics Simulation; Neoplasms - drug therapy; Proteins - chemistry; Proteins - metabolism; Quantum Theory; Review; Reviews; Transition Elements - chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500478

Many transition metal complexes have unique physicochemical properties that can be efficiently exploited in medicinal chemistry for cancer treatment. Traditionally, double‐stranded DNA has been assumed to be the main binding target; however, recent studies have shown that nucleosomal DNA as well as proteins can act as dominant molecular binding partners. This has raised new questions about the molecular determinants that govern DNA versus protein binding selectivity, and has offered new ways to rationalize their biological activity and possible side effects. To address these questions, molecular simulations at an atomistic level of detail have been used to complement, support, and rationalize experimental data. Herein we review some relevant studies—focused on platinum and ruthenium compounds—to illustrate the power of state‐of‐the‐art molecular simulation techniques and to demonstrate how the interplay between molecular simulations and experiments can make important contributions to elucidating the target preferences of some promising transition metal anticancer agents. This contribution aims at providing relevant information that may help in the rational design of novel drug‐discovery strategies. Metal mechanisms: Transition metal anticancer agents can exert their action by binding to different biological targets, including double‐stranded DNA, proteins, and protein/DNA complexes packed in chromatin. Herein we review some relevant studies—based on platinum and ruthenium compounds—showing how the interplay between experimental and computational data has played a key role in clarifying the selectivity for protein versus DNA, thus elucidating relevant drug mechanistic features at the molecular level.