In a previous publication in this journal we have proposed an isolexin-like prototype of a GC minor groove specific ligand. The present paper is devoted to refinements of this prototype (increase in specificity and in DNA binding energy). It is shown that only a very limited improvement can be obtained by increasing the proton accepting capabilities of the heteroaromatic ring systems of the prototype, although these rings interact directly with the proton donating NH2 group of guanine. On the other hand a significant increase both in GC specificity and in DNA binding energy is obtained by replacing the NH linkers of the isolexin by C = C double bonds (yielding what we term "vinylexins"). Specificity is still largely conserved and the DNA binding energy is significantly increased in monocationic vinylexins, which should thus be efficient GC minor groove specific ligands. The outstanding importance for the GC specificity of the C = C linkers is evidenced by the disappearance of this specificity when these linkers are replaced by peptide bonds (peptilexins). On the other hand vinylexins with proton donating heteroaromatic rings are, as expected, AT specific. The vinylexin family may thus represent universal minor groove binding agents susceptible to bind to any given base pair sequence of DNA, following the positioning of their proton donor and proton acceptor rings. This study confirms the insufficiency of purely geometrical and/or hydrogen bonding considerations for the correct estimation of GC versus AT specificity of groove binding ligands. These can only be accounted for by taking into consideration the overall electronic properties of the interacting species and explicitly calculating the energies of complex formation including all the relevant contributions.