Sequence-specific minor groove binding by bis-benzimidazoles: water molecules in ligand recognition.
The binding of two symmetric bis-benzimidazole compounds, 2,2-bis-[4'-(3"-dimethylamino-1"-propyloxy)phenyl]-5,5-bi-1H-benzimidazole and its piperidinpropylphenyl analog, to the minor groove of DNA, have been studied by DNA footprinting, surface plasmon resonance (SPR) methods and molecular dynamics simulations in explicit solvent. The footprinting and SPR methods find that the former compound has enhanced affinity and selectivity for AT sequences in DNA. The molecular modeling studies have suggested that, due to the presence of the oxygen atom in each side chain of the former compound, a water molecule is immobilized and effectively bridges between side chain and DNA base edges via hydrogen bonding interactions. This additional contribution to ligand-DNA interactions would be expected to result in enhanced DNA affinity, as is observed.
Bailly
Christian
C
INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France.
Chessari
Gianni
G
Carrasco
Carolina
C
Joubert
Alexandra
A
Mann
John
J
Wilson
W David
WD
Neidle
Stephen
S
D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D014867:Water / Q000737:chemistry
D001562:Benzimidazoles; D008024:Ligands; D009841:Oligonucleotides; D014867:Water; C009712:bis-benzimidazole; D003850:Deoxyribonuclease I