Discovery of anti-influenza nucleoside triphosphates targeting the catalytic site of A/PR/8/34/H1N1 polymerase.

In an effort to develop potent anti-influenza drugs that inhibit the activity of influenza virus RNA-dependent RNA polymerase (IAV RdRp), a database of nucleoside triphosphates with ~800 molecules were docked with the homology model of IAV RdRp from A/PR/8/34/H1N1 strain. Out of top 12 molecules that bind with higher affinities to the catalytic site of IAV RdRp above and below the PB1 priming loop, only seven molecules decreased the transcriptional activity of the viral RNA polymerase with an IC50 in the range of 0.09-3.58 µM. Molecular docking combining with experimental study indicated that the molecules with linear chain are more effective in inhibiting IAV RdRp replication than the molecules with V-shaped and are cyclic in nature. A correlation between ΔG and LogIC50 for these seven compounds resulted an R 2 value of 0.73. Overall, these newly developed seven nucleoside triphosphates lay a strong foundation for the future development of a new therapeutics that can satisfy the Lipinski's rule of five exhibiting high specificity to the catalytic site of influenza-A viruses.