title: Intercalation processes of copper complexes in DNA.
abstract: The family of anticancer complexes that include the transition metal copper known as Casiopeínas® shows promising results. Two of these complexes are currently in clinical trials. The interaction of these compounds with DNA has been observed experimentally and several hypotheses regarding the mechanism of action have been developed, and these include the generation of reactive oxygen species, phosphate hydrolysis and/or base-pair intercalation. To advance in the understanding on how these ligands interact with DNA, we present a molecular dynamics study of 21 Casiopeínas with a DNA dodecamer using 10 μs of simulation time for each compound. All the complexes were manually inserted into the minor groove as the starting point of the simulations. The binding energy of each complex and the observed representative type of interaction between the ligand and the DNA is reported. With this extended sampling time, we found that four of the compounds spontaneously flipped open a base pair and moved inside the resulting cavity and four compounds formed stacking interactions with the terminal base pairs. The complexes that formed the intercalation pocket led to more stable interactions.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Skaggs Hall 201, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Galindo-Murillo
authors.affiliation: Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México. Avenida Universidad 3000, 04510 México City, Mexico.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Ramos
authors.affiliation: Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México. Avenida Universidad 3000, 04510 México City, Mexico.
authors.forename: Lena
authors.initials: L
authors.lastname: Ruiz-Azuara
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Skaggs Hall 201, University of Utah, Salt Lake City, UT 84112, USA fercor@unam.mx.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Cheatham
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, DF 04510, Mexico Centro Conjunto de Investigación en Química Sustentable UAEMex-UNAM, carretera Toluca-Atlacomulco km 14.5, Toluca, México 50200, Mexico fercor@unam.mx.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cortés-Guzmán
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D056831:Coordination Complexes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D056004:Molecular Dynamics Simulation
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D007364:Intercalating Agents; D003300:Copper; D004247:DNA