Molecular modelling of the interaction of pentamidine analogues with d(CGCGAATTCGCG)2 duplex

A molecular mechanics approach has been used to examine the structure of the complexes formed between d(CGCGAATTCGCG)2 duplex and furan-containing analogues of pentamidine (I-II). The resulting structures of the drug-DNA complexes and their energetics have been examined. From the energetic analysis it appears that van der Waals and electrostatic interactions are more important than specific hydrogen bonds in stabilizing the ligand-duplex complexes. These studies provide rationalizations for the differences in binding behaviour of pentamidine analogues with differing linker chain lengths and aromatic ring substitutions. The superior DNA-binding afforded by II in comparison to pentamidine results from more effective penetration of the minor groove and reduced perturbation factors of molecular structure upon complex formation.