title: Water-mediated binding of agents that target the DNA minor groove.
abstract: Small molecule complexes with DNA that incorporate linking water molecules are rare, and the DB921-DNA complex has provided a unique and well-defined system for analysis of water-mediated binding in the context of a DNA complex. DB921 has a benzimidazole-biphenyl system with terminal amidines that results in a linear conformation that does not possess the appropriate radius of curvature to match the minor groove shape and represents a new paradigm that does not fit the classical model of minor groove interactions. To better understand the role of the bound water molecule observed in the X-ray crystal structure of the DB921 complex, synthetic modifications have been made in the DB921 structure, and the interactions of the new compounds with DNA AT sites have been evaluated with an array of methods, including DNase I footprinting, biosensor-surface plasmon resonance, isothermal titration microcalorimetry, and circular dichroism. The interaction of a key compound, which has the amidine at the phenyl shifted from the para position in DB921 to the meta position, has also been examined by X-ray crystallography. The detailed structural, thermodynamic, and kinetic results provide valuable new information for incorporation of water molecules in the design of new lead scaffolds for targeting DNA in chemical biology and therapeutic applications.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: Sabine
authors.initials: S
authors.lastname: Depauw
authors.forename: Raja
authors.initials: R
authors.lastname: Nhili
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lee
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.forename: Abdelbasset A
authors.initials: AA
authors.lastname: Farahat
authors.forename: Martial
authors.initials: M
authors.lastname: Say
authors.forename: Sarah
authors.initials: S
authors.lastname: Chackal-Catoen
authors.forename: Adalgisa
authors.initials: A
authors.lastname: Batista-Parra
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008970:Molecular Weight; D009690:Nucleic Acid Conformation; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D000578:Amidines; D001562:Benzimidazoles; C506617:DB 921; D014867:Water; D004247:DNA; D003850:Deoxyribonuclease I