Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.

The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes...

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Autores principales:	Mitchell Kramer, Daniel Halleran, Moazur Rahman, Mazhar Iqbal, Muhammad Ikram Anwar, Salwa Sabet, Edward Ackad, Mohammad S Yousef
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b9f7427732cf417797fc96dbb2d4866c
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spelling	oai:doaj.org-article:b9f7427732cf417797fc96dbb2d4866c2021-11-25T06:05:21ZComparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.1932-620310.1371/journal.pone.0104425https://doaj.org/article/b9f7427732cf417797fc96dbb2d4866c2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25111232/?tool=EBIhttps://doaj.org/toc/1932-6203The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity. We have previously developed a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active sites of the NS3 proteases of HCV-1b and 4a in relation to their catalytic activity and drug susceptibility. Here, we improved the methodology, extended the analysis to include genotype 3a (predominant in South Asia including Pakistan), and compared the results of the three genotypes (1b, 3a and 4a). The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease. The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state. These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.Mitchell KramerDaniel HalleranMoazur RahmanMazhar IqbalMuhammad Ikram AnwarSalwa SabetEdward AckadMohammad S YousefPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e104425 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mitchell Kramer Daniel Halleran Moazur Rahman Mazhar Iqbal Muhammad Ikram Anwar Salwa Sabet Edward Ackad Mohammad S Yousef Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
description	The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity. We have previously developed a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active sites of the NS3 proteases of HCV-1b and 4a in relation to their catalytic activity and drug susceptibility. Here, we improved the methodology, extended the analysis to include genotype 3a (predominant in South Asia including Pakistan), and compared the results of the three genotypes (1b, 3a and 4a). The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease. The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state. These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.
format	article
author	Mitchell Kramer Daniel Halleran Moazur Rahman Mazhar Iqbal Muhammad Ikram Anwar Salwa Sabet Edward Ackad Mohammad S Yousef
author_facet	Mitchell Kramer Daniel Halleran Moazur Rahman Mazhar Iqbal Muhammad Ikram Anwar Salwa Sabet Edward Ackad Mohammad S Yousef
author_sort	Mitchell Kramer
title	Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
title_short	Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
title_full	Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
title_fullStr	Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
title_full_unstemmed	Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
title_sort	comparative molecular dynamics simulation of hepatitis c virus ns3/4a protease (genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/b9f7427732cf417797fc96dbb2d4866c
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Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.

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