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 R² 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.

中文翻译：

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发现靶向 A/PR/8/34/H1N1 聚合酶催化位点的抗流感核苷三磷酸。

为了开发抑制流感病毒 RNA 依赖性 RNA 聚合酶 (IAV RdRp) 活性的强效抗流感药物，具有约 800 个分子的三磷酸核苷数据库与来自 A/PR/ 的 IAV RdRp 同源模型对接。 8/34/H1N1 毒株。在与 PB1 引发环上方和下方的 IAV RdRp 催化位点具有更高亲和力的前 12 个分子中，只有 7 个分子降低了病毒 RNA 聚合酶的转录活性，IC ₅₀在 0.09–3.58 µM 范围内。分子对接结合实验研究表明，直链分子比V型分子更能有效抑制IAV RdRp复制，且具有环状结构。Δ G与 LogIC _{50之间的相关性}这七种化合物的R ²值为 0.73。总体而言，这些新开发的七种三磷酸核苷为未来开发一种新疗法奠定了坚实的基础，该疗法可以满足 Lipinski 的五种规则，对甲型流感病毒的催化位点表现出高特异性。