A CRYSTALLOGRAPHIC AND SPECTROSCOPIC STUDY OF THE COMPLEX BETWEEN D(CGCGAATTCGCG)(2) AND 2,5-BIS(4-GUANYLPHENYL)FURAN, AN ANALOG OF BERENIL- STRUCTURAL ORIGINS OF ENHANCED DNA-BINDING AFFINITY
Ca. Laughton et al., A CRYSTALLOGRAPHIC AND SPECTROSCOPIC STUDY OF THE COMPLEX BETWEEN D(CGCGAATTCGCG)(2) AND 2,5-BIS(4-GUANYLPHENYL)FURAN, AN ANALOG OF BERENIL- STRUCTURAL ORIGINS OF ENHANCED DNA-BINDING AFFINITY, Biochemistry, 35(18), 1996, pp. 5655-5661
2,5-Bis(4-guanylphenyl)furan (''furamidine'') is a dicationic minor gr
oove binding drug that has been shown to be more effective than pentam
idine against the Pneumocystis carinii pathogen in an immunosuppressed
rat model. It has a close structural similarity to the antitrypanosom
al drug berenil, differing only in the replacement of the central tria
zene unit with a furan moiety. We have determined the crystal structur
e of the complex between furamidine and the DNA do decamer d(CGCGAATTC
GCG)(2) and compared it to the corresponding berenil complex. We have
also compared the interaction of these two ligands with the same DNA s
equence by UV-visible, fluoresence, and CD spectroscopy. Furamidine sh
ows tighter binding to this sequence (K-eq = 6.7 x 10(6)) than berenil
(K-eq = 6.6 x 10(5)). The crystal structure reveals that, unlike bere
nil, furamidine makes direct hydrogen bond interactions with this DNA
sequence through both amidinium groups to O2 atoms of thymine bases an
d is more isohelical with the minor groove. Molecular mechanics calcul
ations support the hypothesis that these differences result in the imp
roved interaction energy between the ligand and the DNA.