title: Characterization of a novel DNA minor-groove complex.
abstract: Many dicationic amidine compounds bind in the DNA minor groove and have excellent biological activity against a range of infectious diseases. Para-substituted aromatic diamidines such as furamidine, which is currently being tested against trypanosomiasis in humans, and berenil, which is used in animals, are typical examples of this class. Recently, a meta-substituted diamidine, CGP 40215A, has been found to have excellent antitrypanosomal activity. The compound has a linear, conjugated linking group that can be protonated under physiological conditions when the compound interacts with DNA. Structural and molecular dynamics analysis of the DNA complex indicated an unusual AT-specific complex that involved water-mediated H-bonds between one amidine of the compound and DNA bases at the floor of the minor groove. To investigate this unique system in more detail DNase I footprinting, surface plasmon resonance biosensor techniques, linear dichroism, circular dichroism, ultraviolet-visible spectroscopy, and additional molecular dynamics simulations have been conducted. Spectrophotometric titrations of CGP 40215A binding to poly(dAT)(2) have characteristics of DNA-binding-induced spectral changes as well as effects due to binding-induced protonation of the compound linker. Both footprinting and surface plasmon resonance results show that this compound has a high affinity for AT-rich sequences of DNA but very weak binding to GC sequences. The dissociation kinetics of the CGP 40215A-DNA complex are much slower than with similar diamidines such as berenil. The linear dichroism results support a minor-groove complex for the compound in AT DNA sequences. Molecular dynamics studies complement the structural analysis and provide a clear picture of the importance of water in mediating the dynamic interactions between the ligand and the DNA bases in the minor groove.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Binh
authors.initials: B
authors.lastname: Nguyen
authors.forename: Donald
authors.initials: D
authors.lastname: Hamelberg
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Pierre
authors.initials: P
authors.lastname: Colson
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Stanek
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D003198:Computer Simulation; D007700:Kinetics; D046911:Macromolecular Substances; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011067:Poly dA-dT / Q000737:chemistry*; D011089:Polydeoxyribonucleotides / Q000737:chemistry*; D012370:Robenidine / Q000031:analogs & derivatives* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
chemical_list: D046911:Macromolecular Substances; D011089:Polydeoxyribonucleotides; D014867:Water; C102850:bis((3-(aminoiminomethyl)phenyl)methylene)carbonimidic dihydrazide trihydrochloride; D011067:Poly dA-dT; C019530:poly(dC-dG); D012370:Robenidine