Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir

© The Royal Society of Chemistry. Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protea...

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Main Authors: Arthitaya Meeprasert, Supot Hannongbua, Nawee Kungwan, Thanyada Rungrotmongkol
Format: Journal
Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/55271
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Institution: Chiang Mai University
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spelling th-cmuir.6653943832-552712018-09-05T02:53:50Z Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir Arthitaya Meeprasert Supot Hannongbua Nawee Kungwan Thanyada Rungrotmongkol Biochemistry, Genetics and Molecular Biology © The Royal Society of Chemistry. Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protease has become one of the main drug-targets in the design and development of anti-HCV agents. Unfortunately, high mutation rates in HCV have been reported due to the lack of RNA proofreading activity resulting in drug resistance. Herein, all-atom molecular dynamics simulations were employed to understand and illustrate the effects of the NS3/4A D168V mutation on faldaprevir (FDV) and danoprevir (DNV) binding efficiency. The D168V mutation was shown to interrupt the hydrogen bonding network of Q80R155D168R123 embedded in the extended S2 and partial S4 subsites of the NS3 protein and as a result the R123 side chain was displaced and moved out from the binding pocket. By means of MM/PBSA and MM/GBSA binding free energy calculations, the FDV and DNV binding affinities were shown to be significantly reduced by ∼10-15 kcal mol1and ∼4-9 kcal mol1relative to the wild-type complexes, respectively, which somewhat agrees with the experimental resistance folds. 2018-09-05T02:53:50Z 2018-09-05T02:53:50Z 2016-01-01 Journal 17422051 1742206X 2-s2.0-84996848831 10.1039/C6MB00610H https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84996848831&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/55271
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
spellingShingle Biochemistry, Genetics and Molecular Biology
Arthitaya Meeprasert
Supot Hannongbua
Nawee Kungwan
Thanyada Rungrotmongkol
Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir
description © The Royal Society of Chemistry. Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protease has become one of the main drug-targets in the design and development of anti-HCV agents. Unfortunately, high mutation rates in HCV have been reported due to the lack of RNA proofreading activity resulting in drug resistance. Herein, all-atom molecular dynamics simulations were employed to understand and illustrate the effects of the NS3/4A D168V mutation on faldaprevir (FDV) and danoprevir (DNV) binding efficiency. The D168V mutation was shown to interrupt the hydrogen bonding network of Q80R155D168R123 embedded in the extended S2 and partial S4 subsites of the NS3 protein and as a result the R123 side chain was displaced and moved out from the binding pocket. By means of MM/PBSA and MM/GBSA binding free energy calculations, the FDV and DNV binding affinities were shown to be significantly reduced by ∼10-15 kcal mol1and ∼4-9 kcal mol1relative to the wild-type complexes, respectively, which somewhat agrees with the experimental resistance folds.
format Journal
author Arthitaya Meeprasert
Supot Hannongbua
Nawee Kungwan
Thanyada Rungrotmongkol
author_facet Arthitaya Meeprasert
Supot Hannongbua
Nawee Kungwan
Thanyada Rungrotmongkol
author_sort Arthitaya Meeprasert
title Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir
title_short Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir
title_full Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir
title_fullStr Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir
title_full_unstemmed Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir
title_sort effect of d168v mutation in ns3/4a hcv protease on susceptibilities of faldaprevir and danoprevir
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84996848831&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/55271
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