Study of Ribavirin-Nucleic Acids Interaction

The UV-Vis absorption spectra of ribavirin in the absence and presence of calf thymus DNA are presented and discussed in this paper. The molecular structure of ribavirin was investigated by the semiempirical AM1 method, which triggered two polymorphic modifications of the antiviral drug also reported in the literature. Our experimental results point out two types of the binding. The first type involves a non-electrostatic (internal) binding, consisting of the intercalation of drug between the nitrogenous bases of nucleic acid. The second type (an external binding) involves the drug binding to the nucleic acid grooves. In addition, the binding constant of the second process has an order of magnitude greater than the binding constant for the first process, calculated by the Benesi-Hildebrand, Scott, and Scatchard methods, which supposes a 1: 1 binding ratio. Also, the interactions of two polymorphic modifications of ribavirin (V-1 and V-2) with nucleic acids by the molecular mechanic and semiempirical AM1 methods were analyzed. The experimental data pointed out that in the ribavirin-nucleic acid complexes, the 1,2,4-triazole-3-carboxamide chromophore is intercalated between the bases of the nucleic acid sequences, the carboxamidic group is set outside of the nucleic acid sequence toward the major groove, and the 2-hydroxymethyl-tetrahydrofuran-3,4-diol fragment is located in the minor groove. In order to stress the sequence specificity of ribavirin, different models of the nucleic acid sequences containing adenine (A), thymine (T), cytosine (C), and guanine (G) in AAAAAA, TTTTTT, CCCCCC, GGGGGG, ATATAT, CGCGCG, ATCGAT, and CGATCG were used. The theoretical results outline the differences in the contributions of the electrostatic and van der Waals interactions to the total binding energy and the preference of ribavirin for the binding at the sequences of nucleic acids containing adenine and thymine bases.