An In-Silico Investigation of Phytochemicals as Antiviral Agents Against Dengue Fever

Powers, Chelsea N.; Setzer, William N.

The strongest docking (most exothermic) ligands that do not violate Lipinski's rule of five are listed in Table 2 along with their docking energies to the RNA binding site and the ATP binding site. These ligands were selected based on their docking energies compared to the docking energies of the co-crystallized ligands in the ATP binding site, ANP (phosphoaminophosphonic acid adenylate ester, -156.9 kJ/mol) and ADP (adenosine 5'-diphosphate, -142.1 kJ/mol). Note that the phytochemical ligands showed a notable docking preference for the ATP site of DENV helicase over the RNA binding site. The ATP site of DENV helicase is dominated by protonated basic amino acids (Arg463, Lys199, Lys201, Arg460) that form ionic interactions and hydrogen bonds with the phosphate groups of ATP and the co-crystallized ligands ADP or ANP. Additional hydrogenbonding amino acids include Gly196, Gly198, and Thr200. Lys201 and Arg418 form hydrogen-bonds with the adenine moiety. As was the case with DENV protease, the strongest docking class of phytochemicals with DENV helicase ATP site were the chalcones (average E dock = -126.1 kJ/mol) and the stilbenoids (average E dock = -117.6 kJ/mol) while the worst were the terpenoids. The strongest docking ligands were curcumin II (E dock = -164.0 kJ/mol), caffeoyl-pcoumaroyltartaric acid (E dock = -156.2 kJ/mol), balsacone C (E dock = -153.6 kJ/mol), curcumin I (E dock = -153.4 kJ/mol), and angusticornin B (E dock = -152.5 kJ/mol). These ligands dock into the phosphate site of the ATP binding site and not in the adenine site of co-crystallized ADP or ANP. The common structural features of the best docking ligands are two phenolic groups with a flexible linker between them. One of the phenolic groups occupies the phosphate site while the other occupies a site flanked on either side by Arg463 and Arg418 (Figure 3 ). Several cinnamic acid derivatives from black cohosh (Cimicifuga racemosa) [56] have shown exceptional docking to the ATP site of DENV helicase, including cimicifugic acids B and G, cimiciphenol, and cimiracemate D ( Table 2 ).