title: Solution structure of 2-(pyrido[1,2-e]purin-4-yl)amino-ethanol intercalated in the DNA duplex d(CGATCG)2.
abstract: The solution structure of the complex formed between d(CGATCG)(2) and 2-(pyrido[1,2-e]purin-4-yl)amino-ethanol, a new antitumor drug under design, has been resolved using NMR spectroscopy and restrained molecular dynamic simulations. The drug molecule intercalates between each of the CpG dinucleotide steps with its side chain lying in the minor groove. Analysis of NMR data establishes a weak stacking interaction between the intercalated ligand and the DNA bases; however, the drug/DNA affinity is enhanced by a hydrogen bond between the hydroxyl group of the end of the intercalant side chain and the amide group of guanine G6. Unrestrained molecular dynamic simulations performed in a water box confirm the stability of the intercalation model. The structure of the intercalated complex enables insight into the structure-activity relationship, allowing rationalization of the design of new antineoplasic agents.
authors.affiliation: Institut de Biologie Structurale, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France.
authors.forename: A
authors.initials: A
authors.lastname: Favier
authors.forename: M
authors.initials: M
authors.lastname: Blackledge
authors.forename: J P
authors.initials: JP
authors.lastname: Simorre
authors.forename: S
authors.initials: S
authors.lastname: Crouzy
authors.forename: V
authors.initials: V
authors.lastname: Dabouis
authors.forename: A
authors.initials: A
authors.lastname: Gueiffier
authors.forename: D
authors.initials: D
authors.lastname: Marion
authors.forename: J C
authors.initials: JC
authors.lastname: Debouzy
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D003855:Deoxyribose / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry; D007364:Intercalating Agents / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry*; D010755:Organophosphates / Q000737:chemistry; D011522:Protons; D011687:Purines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D012996:Solutions; D013816:Thermodynamics
chemical_list: C436410:2-(pyrido(1,2-e)purin-4-yl)amino-ethanol; D000970:Antineoplastic Agents; D007093:Imidazoles; D007364:Intercalating Agents; D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides; D010755:Organophosphates; D011522:Protons; D011687:Purines; D011725:Pyridines; D012996:Solutions; D003855:Deoxyribose; D004247:DNA; C001439:imidazo(1,2-a)pyridine