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

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.