HCV p7 protein is a cation-selective ion channel, playing an essential role during the life cycle of HCV viruses. To understand the cation-selective mechanism, we constructed a hexameric model in lipid bilayers of HCV p7 protein for HCB JFH-1 strain, genotype 2a. In this structural model, His9 and Val6 were key factors for the HCV cation-selective ion channel. The histidine residues at position 9 in the hexameric model formed a first gate for HCV p7 channel, acting as a selectivity filter for cations. The valines mentioned above formed a second gate for HCV p7 channel, serving as a hydrophobic filter for the dehydrated cations. The binding pocket for the channel blockers, e.g., amantadine and rimantadine, was composed of residues 20-26 in H2 helix and 52-60 in H3 helix in i + 2 monomer. However, the molecular volumes for both amantadine and rimantadine were too small for the binding pocket of HCV p7 channel. Thus, designing a compound similar with rimantadine and having much larger volume would be an effective strategy for discovering inhibitors against HCV p7 channel. To achieve this point, we used rimantadine as a structural template to search ChEMBL database for the candidates employing favorable binding affinities to HCV p7 channel. As a result, six candidates were identified to have potential to be novel inhibitors against HCV p7 channel.

中文翻译：

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HCV p7通道的计算研究：深入了解HCV抑制剂设计的新策略。

HCV p7蛋白是一个阳离子选择性离子通道，在HCV病毒的生命周期中起着至关重要的作用。为了了解阳离子选择性机制，我们针对HCB JFH-1菌株（基因型2a）在HCV p7蛋白的脂质双层中构建了六聚体模型。在此结构模型中，His9和Val6是HCV阳离子选择性离子通道的关键因素。六聚体模型中位置9处的组氨酸残基形成HCV p7通道的第一个门，充当阳离子的选择性过滤器。上述缬氨酸形成了HCV p7通道的第二个门，用作脱水阳离子的疏水过滤器。通道阻断剂（例如金刚烷胺和金刚乙胺）的结合口袋由i + 2单体中H2螺旋中的20-26和H3螺旋中的52-60残基组成。然而，金刚烷胺和金刚乙胺的分子体积都太小，无法与HCV p7通道的结合袋结合。因此，设计与金刚乙胺相似且体积更大的化合物将是发现针对HCV p7通道抑制剂的有效策略。为了达到这一点，我们使用金刚烷胺作为结构模板来搜索ChEMBL数据库，以寻找对HCV p7通道具有良好结合亲和力的候选物。结果，确定了六种候选药物，它们可能是针对HCV p7通道的新型抑制剂。我们使用金刚烷胺作为结构模板来搜索ChEMBL数据库，以寻找对HCV p7通道具有良好结合亲和力的候选物。结果，确定了六种候选药物，它们可能是针对HCV p7通道的新型抑制剂。我们使用金刚烷胺作为结构模板来搜索ChEMBL数据库，以寻找对HCV p7通道具有良好结合亲和力的候选物。结果，确定了六种候选药物，它们可能是针对HCV p7通道的新型抑制剂。