In silico analysis of heparin and chondroitin sulfate binding mechanisms of the antiprotozoal drug berenil and pentamidine.

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.