<p>Modeling cationic small-molecule inhibitors of G-quadruplex structures faces controversial opinions as to whether stabilization of the complex can occur by the interaction of the inhibitor with the negatively charged phosphate backbone. The challenge has been taken here of bringing light on such a awful situation by disentangling the energies of interaction of G-quadruplex residues with the inhibitor in a series of representative G-quadruplex complexes. The problem was addressed to computer simulations in the lack of suitable experimental approaches. It emerged that the phosphate contribution can range from dominating to nil, according to whether, in a dynamic course, the inhibitor cationic center can get close to a phosphate group or remain out of the range of coulombic attraction from all them, thus providing guidelines for tailoring the inhibitor toward the best possible stabilization of the complex.</p> Graphical Abstract <p></p>