The computational search of chemical libraries has been used as a powerful tool for the rapid discovery of candidate compounds. To find small molecules with anti-feline infectious peritonitis virus (FIPV) properties, we utilized a virtual screening technique to identify the active site on the viral protease for the binding of the available natural compounds. The protease 3CL (3CLpro) plays an important role in the replication cycle of FIPV and other viruses within the family Coronaviridae. The 15 best-ranked candidate consensus compounds, based on three docking tools, were evaluated for further assays. The protease inhibitor assay on recombinant FIPV 3CLpro was performed to screen the inhibitory effect of the candidate compounds with IC50 ranging from 6.36 ± 2.15 to 78.40 ± 2.60 μM. As determined by the cell-based assay, the compounds NSC345647, NSC87511, and NSC343256 showed better EC50 values than the broad-spectrum antiviral drug ribavirin and the protease inhibitor lopinavir, under all the test conditions including pre-viral entry, post-viral entry, and prophylactic activity. The NSC87511 particularly yielded the best selective index (>4; range of SI = 13.80-22.90). These results indicated that the natural small-molecular compounds specifically targeted the 3CLpro of FIPV and inhibited its replication. Structural modification of these compounds may generate a higher anti-viral potency for the further development of a novel therapy against FIP.

中文翻译：

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对猫传染性腹膜炎病毒的3CL蛋白酶靶向的小分子和天然化合物进行计算机和体外分析。

化学文库的计算搜索已用作快速发现候选化合物的强大工具。为了找到具有抗猫传染性腹膜炎病毒（FIPV）特性的小分子，我们利用虚拟筛选技术来识别病毒蛋白酶上的活性位点，以结合可用的天然化合物。蛋白酶3CL（3CLpro）在冠状病毒科的FIPV和其他病毒的复制周期中起着重要作用。基于三种对接工具，对15种排名最高的候选共有化合物进行了评估，以用于进一步的分析。进行了针对重组FIPV 3CLpro的蛋白酶抑制剂测定，以筛选候选化合物的抑制作用，IC50范围为6.36±2.15至78.40±2.60μM。通过基于细胞的分析确定，化合物NSC345647 在所有测试条件下，包括病毒进入前，病毒进入后和预防活性，NSC87511和NSC343256的EC50值均优于广谱抗病毒药物利巴韦林和蛋白酶抑制剂洛匹那韦。NSC87511特别产生了最佳的选择指数（> 4； SI范围为13.80-22.90）。这些结果表明，天然小分子化合物特异性靶向FIPV的3CLpro并抑制了其复制。这些化合物的结构修饰可能会产生更高的抗病毒效力，以进一步开发针对FIP的新疗法。NSC87511特别产生了最佳的选择指数（> 4； SI范围为13.80-22.90）。这些结果表明，天然小分子化合物特异性靶向FIPV的3CLpro并抑制了其复制。这些化合物的结构修饰可能会产生更高的抗病毒效力，以进一步开发针对FIP的新疗法。NSC87511特别产生了最佳的选择指数（> 4； SI范围为13.80-22.90）。这些结果表明，天然小分子化合物特异性靶向FIPV的3CLpro并抑制了其复制。这些化合物的结构修饰可能会产生更高的抗病毒效力，以进一步开发针对FIP的新疗法。