chondroitin-sulfates and diminazene-aceturate

Glycosaminoglycans (GAGs) is a particular class of linear anionic periodic polysaccharides, which play a key role in many cell signaling processes in the extracellular matrix by direct interactions with multiple proteins targets. Because of their periodic nature resulting in experimental challenges to study these molecules, computational approaches recently proved to be successful in complementing the experiments aimed to understand GAG interactions. However, the aspect of GAG binding of small, pharmacologically active molecules is still essentially understudied despite its significance. In this work, we apply computational approaches to rigorously characterize the interactions between GAGs and two trypanosoma active DNA targeting agents, berenil and pentamidine, which mainly differ in the structure of their intramolecular linkers connecting two benzamidine moieties. We thoroughly analyze their binding to heparin and chondroitin 6-sulfate in terms of dynamics, energetics and properties of π-stacked oligomeric structures of the drug molecules formed upon GAG association. Our work contributes to the general understanding of biologically relevant interactions between GAGs and small molecules which has potential impact in drug pharmacology and related therapeutic modalities.

Topics: Antiprotozoal Agents; Chondroitin Sulfates; Computer Simulation; Diminazene; Heparin; Hydrogen Bonding; Molecular Conformation; Molecular Dynamics Simulation; Pentamidine; Quantum Theory; Thermodynamics

It is shown that the antiprotozoal drugs berenil and pentamidine, conventional minor groove binders of DNA, form non-covalent complexes with polyanionic glycosaminoglycans. Induced circular dichroism (CD) spectra as well as UV hypochromism confirmed drug binding to the asymmetric template of heparin and chondroitin 6-sulfate. The biphasic nature of the CD signals refers to intermolecular chiral exciton coupling between the dicationic guest molecules forming a right- or a left-handed helical array along the GAG chains. Quantitative evaluation of the spectroscopic data measured in pH 7.0 buffer solution (80 mM NaCl) indicated a higher (Ka ∼ 10(6) M(-1) for berenil) and a lower (Ka ∼ 10(5) M(-1) for pentamidine) affinity heparin binding of these agents, similar to that reported for DNA. Drug-chondroitin sulfate complexes (Ka ∼ 10(4)-10(5) M(-1)) could be detected only at low ionic strength. These results imply that besides nucleic acids, GAGs may be another pharmacological targets for diarylamidine drugs.

Topics: Antiprotozoal Agents; Chondroitin Sulfates; Circular Dichroism; Diminazene; DNA; Glycosaminoglycans; Pentamidine; Spectrophotometry, Ultraviolet