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Inhibitor Development against p7 Channel in Hepatitis C Virus
Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protei...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961618/ https://www.ncbi.nlm.nih.gov/pubmed/33802584 http://dx.doi.org/10.3390/molecules26051350 |
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author | Wei, Shukun Hu, Xiaoyou Du, Lingyu Zhao, Linlin Xue, Hongjuan Liu, Chaolun Chou, James J. Zhong, Jin Tong, Yimin Wang, Shuqing OuYang, Bo |
author_facet | Wei, Shukun Hu, Xiaoyou Du, Lingyu Zhao, Linlin Xue, Hongjuan Liu, Chaolun Chou, James J. Zhong, Jin Tong, Yimin Wang, Shuqing OuYang, Bo |
author_sort | Wei, Shukun |
collection | PubMed |
description | Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates. |
format | Online Article Text |
id | pubmed-7961618 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79616182021-03-17 Inhibitor Development against p7 Channel in Hepatitis C Virus Wei, Shukun Hu, Xiaoyou Du, Lingyu Zhao, Linlin Xue, Hongjuan Liu, Chaolun Chou, James J. Zhong, Jin Tong, Yimin Wang, Shuqing OuYang, Bo Molecules Article Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates. MDPI 2021-03-03 /pmc/articles/PMC7961618/ /pubmed/33802584 http://dx.doi.org/10.3390/molecules26051350 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wei, Shukun Hu, Xiaoyou Du, Lingyu Zhao, Linlin Xue, Hongjuan Liu, Chaolun Chou, James J. Zhong, Jin Tong, Yimin Wang, Shuqing OuYang, Bo Inhibitor Development against p7 Channel in Hepatitis C Virus |
title | Inhibitor Development against p7 Channel in Hepatitis C Virus |
title_full | Inhibitor Development against p7 Channel in Hepatitis C Virus |
title_fullStr | Inhibitor Development against p7 Channel in Hepatitis C Virus |
title_full_unstemmed | Inhibitor Development against p7 Channel in Hepatitis C Virus |
title_short | Inhibitor Development against p7 Channel in Hepatitis C Virus |
title_sort | inhibitor development against p7 channel in hepatitis c virus |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961618/ https://www.ncbi.nlm.nih.gov/pubmed/33802584 http://dx.doi.org/10.3390/molecules26051350 |
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