Molecular interactions of the anticancer agent ellipticine with glycosaminoglycans by in silico analysis

The anticancer agent ellipticine (ELP) functions as a DNA intercalating drug. Depending on the pH of the medium, it exists both in a neutral and a protonated form. In acidic extracellular microenvironment characteristic to malignant tissues, charged ELP molecules can also bind to glycosaminoglycans (GAGs), linear anionic periodic polysaccharides, which interact with various protein targets affecting diverse cellular events. Although a previous experimental work indicated specific GAG binding of protonated ELP, the underlying molecular mechanisms remain to be elucidated. From a computational point of view, analysis of molecular systems containing GAGs is challenging due to their high flexibility, variability in sulfation patterns and a key role of electrostatics and solvent-mediated interactions. In the present study, molecular dynamics-based approaches were employed to model ELP-GAG interactions in order to unveil the atomistic details of this biologically relevant molecular system. We characterized dynamic and energetic properties of three kinds of ELP-GAG complexes to rationalize and complement the available experimental data. The results reported herein provide insight into possible molecular pathways by which biological actions of ELP are mediated.