Computational Study of HCV p7 Channel: Insight into a New Strategy for HCV Inhibitor Design

• Published in: Interdisciplinary sciences : computational life sciences Vol. 11; no. 2; pp. 292 - 299
• Main Authors: Ying, Beili, Pang, Shichao, Yang, Junchen, Zhong, Yang, Wang, Jingfang
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2019; Springer Nature B.V
• Subjects: Amantadine; Antiviral Agents - pharmacology; Binding; Binding Sites; Biomedical and Life Sciences; Cations; Computational Biology - methods; Computational Biology/Bioinformatics; Computational Science and Engineering; Computer Appl. in Life Sciences; Computer applications; Dehydration; Drug Design; Genotypes; Health Sciences; Hepacivirus - drug effects; Hepacivirus - metabolism; Histidine; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Inhibitors; Ion channels; Ion Channels - chemistry; Ion Channels - metabolism; Life cycle engineering; Life cycles; Life Sciences; Lipid bilayers; Lipids; Mathematical and Computational Physics; Medicine; Models, Molecular; Original Research Article; p7 Protein; Protein Structure, Secondary; Proteins; Residues; Rimantadine - chemistry; Rimantadine - pharmacology; Selectivity; Statistics for Life Sciences; Structure-Activity Relationship; Theoretical; Theoretical and Computational Chemistry; Viral Proteins - chemistry; Viral Proteins - metabolism; P7 channel; Structure-based drug design; Hepatitis C virus; Molecular modeling
• ISSN: 1913-2751; 1867-1462
• DOI: 10.1007/s12539-018-0306-3

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.