title: Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies.
abstract: 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.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palermo
authors.affiliation: CNR-IOM-Democritos National Simulation Center, c/o SISSA, via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Magistrato
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Riedel
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Thibaud
authors.initials: T
authors.lastname: von Erlach
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
authors.forename: Curt A
authors.initials: CA
authors.lastname: Davey
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland. ursula.roethlisberger@epfl.ch.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rothlisberger
mesh_terms: D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory; D028561:Transition Elements / Q000737:chemistry*
chemical_list: D002843:Chromatin; D056831:Coordination Complexes; D011506:Proteins; D028561:Transition Elements; D004247:DNA; D002256:Carbonic Anhydrases
keywords: antitumor agents; drug design; medicinal chemistry; metal complexes; molecular dynamics