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In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure

BACKGROUND: The recently solved solution structure of HCV (hepatitis C virus) p7 ion channel provides a solid structure basis for drug design against HCV infection. In the p7 channel the ligand amantadine (or rimantadine) was determined in a hydrophobic pocket. However the pharmocophore (−NH(2)) of...

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Autores principales: Du, Qi-Shi, Wang, Shu-Qing, Chen, Dong, Meng, Jian-Zong, Huang, Ri-Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979700/
https://www.ncbi.nlm.nih.gov/pubmed/24714586
http://dx.doi.org/10.1371/journal.pone.0093613
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author Du, Qi-Shi
Wang, Shu-Qing
Chen, Dong
Meng, Jian-Zong
Huang, Ri-Bo
author_facet Du, Qi-Shi
Wang, Shu-Qing
Chen, Dong
Meng, Jian-Zong
Huang, Ri-Bo
author_sort Du, Qi-Shi
collection PubMed
description BACKGROUND: The recently solved solution structure of HCV (hepatitis C virus) p7 ion channel provides a solid structure basis for drug design against HCV infection. In the p7 channel the ligand amantadine (or rimantadine) was determined in a hydrophobic pocket. However the pharmocophore (−NH(2)) of the ligand was not assigned a specific binding site. RESULTS: The possible binding sites for amino group of adamantane derivatives is studied based on the NMR structure of p7 channel using QM calculation and molecular modeling. In the hydrophobic cavity and nearby three possible binding sites are proposed: His17, Phe20, and Trp21. The ligand binding energies at the three binding sites are studied using high level QM method CCSD(T)/6–311+G(d,p) and AutoDock calculations, and the interaction details are analyzed. The potential application of the binding sites for rational inhibitor design are discussed. CONCLUSIONS: Some useful viewpoints are concluded as follows. (1) The amino group (−NH(2)) of adamantane derivatives is protonated (−NH(3) (+)), and the positively charged cation may form cation-π interactions with aromatic amino acids. (2) The aromatic amino acids (His17, Phe20, and Trp21) are the possible binding sites for the protonated amino group (−NH(3) (+)) of adamantane derivatives, and the cation-π bond energies are 3 to 5 times stronger than the energies of common hydrogen bonds. (3) The higher inhibition potent of rimantadine than amantadine probably because of its higher pK(a) value (pK(a) = 10.40) and the higher positive charge in the amino group. The potential application of p7 channel structure for inhibitor design is discussed.
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spelling pubmed-39797002014-04-11 In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure Du, Qi-Shi Wang, Shu-Qing Chen, Dong Meng, Jian-Zong Huang, Ri-Bo PLoS One Research Article BACKGROUND: The recently solved solution structure of HCV (hepatitis C virus) p7 ion channel provides a solid structure basis for drug design against HCV infection. In the p7 channel the ligand amantadine (or rimantadine) was determined in a hydrophobic pocket. However the pharmocophore (−NH(2)) of the ligand was not assigned a specific binding site. RESULTS: The possible binding sites for amino group of adamantane derivatives is studied based on the NMR structure of p7 channel using QM calculation and molecular modeling. In the hydrophobic cavity and nearby three possible binding sites are proposed: His17, Phe20, and Trp21. The ligand binding energies at the three binding sites are studied using high level QM method CCSD(T)/6–311+G(d,p) and AutoDock calculations, and the interaction details are analyzed. The potential application of the binding sites for rational inhibitor design are discussed. CONCLUSIONS: Some useful viewpoints are concluded as follows. (1) The amino group (−NH(2)) of adamantane derivatives is protonated (−NH(3) (+)), and the positively charged cation may form cation-π interactions with aromatic amino acids. (2) The aromatic amino acids (His17, Phe20, and Trp21) are the possible binding sites for the protonated amino group (−NH(3) (+)) of adamantane derivatives, and the cation-π bond energies are 3 to 5 times stronger than the energies of common hydrogen bonds. (3) The higher inhibition potent of rimantadine than amantadine probably because of its higher pK(a) value (pK(a) = 10.40) and the higher positive charge in the amino group. The potential application of p7 channel structure for inhibitor design is discussed. Public Library of Science 2014-04-08 /pmc/articles/PMC3979700/ /pubmed/24714586 http://dx.doi.org/10.1371/journal.pone.0093613 Text en © 2014 Du et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Du, Qi-Shi
Wang, Shu-Qing
Chen, Dong
Meng, Jian-Zong
Huang, Ri-Bo
In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure
title In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure
title_full In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure
title_fullStr In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure
title_full_unstemmed In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure
title_short In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure
title_sort in depth analysis on the binding sites of adamantane derivatives in hcv (hepatitis c virus) p7 channel based on the nmr structure
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979700/
https://www.ncbi.nlm.nih.gov/pubmed/24714586
http://dx.doi.org/10.1371/journal.pone.0093613
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