PandemieGrippaleV1, PascalFrancis, Corpus, bibRecord, 000173

Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations

Identifieur interne : 000173 ( PascalFrancis/Corpus ); précédent : 000172; suivant : 000174

Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations

Auteurs : PEICHEN PAN ; LIN LI ; YOUYONG LI ; DAN LI ; TINGJUN HOU

Source :

Antiviral research [ 0166-3542 ] ; 2013.

RBID : Pascal:14-0009028

Descripteurs français

Pascal (Inist)
- Sensibilité, Antiviral, Médicament, Mutation, Exo-α-sialidase, Dynamique moléculaire, Simulation, Energie libre, Calcul, Grippe, Inhibiteur neuraminidase, Résistance traitement, Influenzavirus A(H1N1), Virus grippal A(H1N1).

English descriptors

KwdEn :
- Antiviral, Calculation, Drug, Exo-α-sialidase, Free energy, Influenza, Influenza A (H1N1), Molecular dynamics, Mutation, Neuraminidase inhibitor, Sensitivity, Simulation, Treatment resistance.

Abstract

Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV > PRV > OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

A01	`01`	`1`		`@0 0166-3542`
A02	`01`			`@0 ARSRDR`
A03		`1`		`@0 Antivir. res.`
A05				`@2 100`
A06				`@2 2`
A08	`01`	`1`	`ENG`	`@1 Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations`
A11	`01`	`1`		`@1 PEICHEN PAN`
A11	`02`	`1`		`@1 LIN LI`
A11	`03`	`1`		`@1 YOUYONG LI`
A11	`04`	`1`		`@1 DAN LI`
A11	`05`	`1`		`@1 TINGJUN HOU`
A14	`01`			`@1 Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University @2 Suzhou, Jiangsu 215123 @3 CHN @Z 1 aut. @Z 2 aut. @Z 3 aut. @Z 5 aut.`
A14	`02`			`@1 College of Pharmaceutical Sciences, Zhejiang University @2 Hangzhou, Zhejiang 310058 @3 CHN @Z 4 aut. @Z 5 aut.`
A20				`@1 356-364`
A21				`@1 2013`
A23	`01`			`@0 ENG`
A43	`01`			`@1 INIST @2 18839 @5 354000507415610090`
A44				`@0 0000 @1 © 2014 INIST-CNRS. All rights reserved.`
A45				`@0 1 p.1/2`
A47	`01`	`1`		`@0 14-0009028`
A60				`@1 P`
A61				`@0 A`
A64	`01`	`1`		`@0 Antiviral research`
A66	`01`			`@0 GBR`
C01	`01`		`ENG`	@0 Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV > PRV > OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance.
C02	`01`	`X`		`@0 002B02S05`
C02	`02`	`X`		`@0 002B05C02C`
C03	`01`	`X`	`FRE`	`@0 Sensibilité @5 01`
C03	`01`	`X`	`ENG`	`@0 Sensitivity @5 01`
C03	`01`	`X`	`SPA`	`@0 Sensibilidad @5 01`
C03	`02`	`X`	`FRE`	`@0 Antiviral @5 02`
C03	`02`	`X`	`ENG`	`@0 Antiviral @5 02`
C03	`02`	`X`	`SPA`	`@0 Antiviral @5 02`
C03	`03`	`X`	`FRE`	`@0 Médicament @5 03`
C03	`03`	`X`	`ENG`	`@0 Drug @5 03`
C03	`03`	`X`	`SPA`	`@0 Medicamento @5 03`
C03	`04`	`X`	`FRE`	`@0 Mutation @5 04`
C03	`04`	`X`	`ENG`	`@0 Mutation @5 04`
C03	`04`	`X`	`SPA`	`@0 Mutación @5 04`
C03	`05`	`X`	`FRE`	`@0 Exo-α-sialidase @2 FE @5 05`
C03	`05`	`X`	`ENG`	`@0 Exo-α-sialidase @2 FE @5 05`
C03	`05`	`X`	`SPA`	`@0 Exo-α-sialidase @2 FE @5 05`
C03	`06`	`X`	`FRE`	`@0 Dynamique moléculaire @5 06`
C03	`06`	`X`	`ENG`	`@0 Molecular dynamics @5 06`
C03	`06`	`X`	`SPA`	`@0 Dinámica molecular @5 06`
C03	`07`	`X`	`FRE`	`@0 Simulation @5 07`
C03	`07`	`X`	`ENG`	`@0 Simulation @5 07`
C03	`07`	`X`	`SPA`	`@0 Simulación @5 07`
C03	`08`	`X`	`FRE`	`@0 Energie libre @5 08`
C03	`08`	`X`	`ENG`	`@0 Free energy @5 08`
C03	`08`	`X`	`SPA`	`@0 Energía libre @5 08`
C03	`09`	`X`	`FRE`	`@0 Calcul @5 09`
C03	`09`	`X`	`ENG`	`@0 Calculation @5 09`
C03	`09`	`X`	`SPA`	`@0 Cálculo @5 09`
C03	`10`	`X`	`FRE`	`@0 Grippe @5 10`
C03	`10`	`X`	`ENG`	`@0 Influenza @5 10`
C03	`10`	`X`	`SPA`	`@0 Gripe @5 10`
C03	`11`	`X`	`FRE`	`@0 Inhibiteur neuraminidase @2 FR @5 11`
C03	`11`	`X`	`ENG`	`@0 Neuraminidase inhibitor @2 FR @5 11`
C03	`11`	`X`	`SPA`	`@0 Inhibidor neuraminidas @2 FR @5 11`
C03	`12`	`X`	`FRE`	`@0 Résistance traitement @5 12`
C03	`12`	`X`	`ENG`	`@0 Treatment resistance @5 12`
C03	`12`	`X`	`SPA`	`@0 Resistencia tratamiento @5 12`
C03	`13`	`X`	`FRE`	`@0 Influenzavirus A(H1N1) @4 INC @5 86`
C03	`14`	`X`	`FRE`	`@0 Virus grippal A(H1N1) @4 CD @5 96`
C03	`14`	`X`	`ENG`	`@0 Influenza A (H1N1) @4 CD @5 96`
C07	`01`	`X`	`FRE`	`@0 Glycosidases @2 FE`
C07	`01`	`X`	`ENG`	`@0 Glycosidases @2 FE`
C07	`01`	`X`	`SPA`	`@0 Glycosidases @2 FE`
C07	`02`	`X`	`FRE`	`@0 Glycosylases @2 FE`
C07	`02`	`X`	`ENG`	`@0 Glycosylases @2 FE`
C07	`02`	`X`	`SPA`	`@0 Glycosylases @2 FE`
C07	`03`	`X`	`FRE`	`@0 Hydrolases @2 FE`
C07	`03`	`X`	`ENG`	`@0 Hydrolases @2 FE`
C07	`03`	`X`	`SPA`	`@0 Hydrolases @2 FE`
C07	`04`	`X`	`FRE`	`@0 Enzyme @2 FE`
C07	`04`	`X`	`ENG`	`@0 Enzyme @2 FE`
C07	`04`	`X`	`SPA`	`@0 Enzima @2 FE`
C07	`05`	`X`	`FRE`	`@0 Virose`
C07	`05`	`X`	`ENG`	`@0 Viral disease`
C07	`05`	`X`	`SPA`	`@0 Virosis`
C07	`06`	`X`	`FRE`	`@0 Infection`
C07	`06`	`X`	`ENG`	`@0 Infection`
C07	`06`	`X`	`SPA`	`@0 Infección`
N21				`@1 006`
N44	`01`			`@1 OTO`
N82				`@1 OTO`

Format Inist (serveur)

NO :	PASCAL 14-0009028 INIST
ET :	Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations
AU :	PEICHEN PAN; LIN LI; YOUYONG LI; DAN LI; TINGJUN HOU
AF :	Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University/Suzhou, Jiangsu 215123/Chine (1 aut., 2 aut., 3 aut., 5 aut.); College of Pharmaceutical Sciences, Zhejiang University/Hangzhou, Zhejiang 310058/Chine (4 aut., 5 aut.)
DT :	Publication en série; Niveau analytique
SO :	Antiviral research; ISSN 0166-3542; Coden ARSRDR; Royaume-Uni; Da. 2013; Vol. 100; No. 2; Pp. 356-364; Bibl. 1 p.1/2
LA :	Anglais
EA :	Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV > PRV > OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance.
CC :	002B02S05; 002B05C02C
FD :	Sensibilité; Antiviral; Médicament; Mutation; Exo-α-sialidase; Dynamique moléculaire; Simulation; Energie libre; Calcul; Grippe; Inhibiteur neuraminidase; Résistance traitement; Influenzavirus A(H1N1); Virus grippal A(H1N1)
FG :	Glycosidases; Glycosylases; Hydrolases; Enzyme; Virose; Infection
ED :	Sensitivity; Antiviral; Drug; Mutation; Exo-α-sialidase; Molecular dynamics; Simulation; Free energy; Calculation; Influenza; Neuraminidase inhibitor; Treatment resistance; Influenza A (H1N1)
EG :	Glycosidases; Glycosylases; Hydrolases; Enzyme; Viral disease; Infection
SD :	Sensibilidad; Antiviral; Medicamento; Mutación; Exo-α-sialidase; Dinámica molecular; Simulación; Energía libre; Cálculo; Gripe; Inhibidor neuraminidas; Resistencia tratamiento
LO :	INIST-18839.354000507415610090
ID :	14-0009028

Links to Exploration step

Pascal:14-0009028

Le document en format XML

<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations</title>
<author><name sortKey="Peichen Pan" sort="Peichen Pan" uniqKey="Peichen Pan" last="Peichen Pan">PEICHEN PAN</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Lin Li" sort="Lin Li" uniqKey="Lin Li" last="Lin Li">LIN LI</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Youyong Li" sort="Youyong Li" uniqKey="Youyong Li" last="Youyong Li">YOUYONG LI</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Dan Li" sort="Dan Li" uniqKey="Dan Li" last="Dan Li">DAN LI</name>
<affiliation><inist:fA14 i1="02"><s1>College of Pharmaceutical Sciences, Zhejiang University</s1>
<s2>Hangzhou, Zhejiang 310058</s2>
<s3>CHN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Tingjun Hou" sort="Tingjun Hou" uniqKey="Tingjun Hou" last="Tingjun Hou">TINGJUN HOU</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
<affiliation><inist:fA14 i1="02"><s1>College of Pharmaceutical Sciences, Zhejiang University</s1>
<s2>Hangzhou, Zhejiang 310058</s2>
<s3>CHN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">INIST</idno>
<idno type="inist">14-0009028</idno>
<date when="2013">2013</date>
<idno type="stanalyst">PASCAL 14-0009028 INIST</idno>
<idno type="RBID">Pascal:14-0009028</idno>
<idno type="wicri:Area/PascalFrancis/Corpus">000173</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations</title>
<author><name sortKey="Peichen Pan" sort="Peichen Pan" uniqKey="Peichen Pan" last="Peichen Pan">PEICHEN PAN</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Lin Li" sort="Lin Li" uniqKey="Lin Li" last="Lin Li">LIN LI</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Youyong Li" sort="Youyong Li" uniqKey="Youyong Li" last="Youyong Li">YOUYONG LI</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Dan Li" sort="Dan Li" uniqKey="Dan Li" last="Dan Li">DAN LI</name>
<affiliation><inist:fA14 i1="02"><s1>College of Pharmaceutical Sciences, Zhejiang University</s1>
<s2>Hangzhou, Zhejiang 310058</s2>
<s3>CHN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Tingjun Hou" sort="Tingjun Hou" uniqKey="Tingjun Hou" last="Tingjun Hou">TINGJUN HOU</name>
<affiliation><inist:fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
<affiliation><inist:fA14 i1="02"><s1>College of Pharmaceutical Sciences, Zhejiang University</s1>
<s2>Hangzhou, Zhejiang 310058</s2>
<s3>CHN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Antiviral research</title>
<title level="j" type="abbreviated">Antivir. res.</title>
<idno type="ISSN">0166-3542</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Antiviral research</title>
<title level="j" type="abbreviated">Antivir. res.</title>
<idno type="ISSN">0166-3542</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term>
<term>Calculation</term>
<term>Drug</term>
<term>Exo-α-sialidase</term>
<term>Free energy</term>
<term>Influenza</term>
<term>Influenza A (H1N1)</term>
<term>Molecular dynamics</term>
<term>Mutation</term>
<term>Neuraminidase inhibitor</term>
<term>Sensitivity</term>
<term>Simulation</term>
<term>Treatment resistance</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Sensibilité</term>
<term>Antiviral</term>
<term>Médicament</term>
<term>Mutation</term>
<term>Exo-α-sialidase</term>
<term>Dynamique moléculaire</term>
<term>Simulation</term>
<term>Energie libre</term>
<term>Calcul</term>
<term>Grippe</term>
<term>Inhibiteur neuraminidase</term>
<term>Résistance traitement</term>
<term>Influenzavirus A(H1N1)</term>
<term>Virus grippal A(H1N1)</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV > PRV > OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance.</div>
</front>
</TEI>
<inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0166-3542</s0>
</fA01>
<fA02 i1="01"><s0>ARSRDR</s0>
</fA02>
<fA03 i2="1"><s0>Antivir. res.</s0>
</fA03>
<fA05><s2>100</s2>
</fA05>
<fA06><s2>2</s2>
</fA06>
<fA08 i1="01" i2="1" l="ENG"><s1>Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations</s1>
</fA08>
<fA11 i1="01" i2="1"><s1>PEICHEN PAN</s1>
</fA11>
<fA11 i1="02" i2="1"><s1>LIN LI</s1>
</fA11>
<fA11 i1="03" i2="1"><s1>YOUYONG LI</s1>
</fA11>
<fA11 i1="04" i2="1"><s1>DAN LI</s1>
</fA11>
<fA11 i1="05" i2="1"><s1>TINGJUN HOU</s1>
</fA11>
<fA14 i1="01"><s1>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University</s1>
<s2>Suzhou, Jiangsu 215123</s2>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</fA14>
<fA14 i1="02"><s1>College of Pharmaceutical Sciences, Zhejiang University</s1>
<s2>Hangzhou, Zhejiang 310058</s2>
<s3>CHN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</fA14>
<fA20><s1>356-364</s1>
</fA20>
<fA21><s1>2013</s1>
</fA21>
<fA23 i1="01"><s0>ENG</s0>
</fA23>
<fA43 i1="01"><s1>INIST</s1>
<s2>18839</s2>
<s5>354000507415610090</s5>
</fA43>
<fA44><s0>0000</s0>
<s1>© 2014 INIST-CNRS. All rights reserved.</s1>
</fA44>
<fA45><s0>1 p.1/2</s0>
</fA45>
<fA47 i1="01" i2="1"><s0>14-0009028</s0>
</fA47>
<fA60><s1>P</s1>
</fA60>
<fA61><s0>A</s0>
</fA61>
<fA64 i1="01" i2="1"><s0>Antiviral research</s0>
</fA64>
<fA66 i1="01"><s0>GBR</s0>
</fA66>
<fC01 i1="01" l="ENG"><s0>Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV > PRV > OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance.</s0>
</fC01>
<fC02 i1="01" i2="X"><s0>002B02S05</s0>
</fC02>
<fC02 i1="02" i2="X"><s0>002B05C02C</s0>
</fC02>
<fC03 i1="01" i2="X" l="FRE"><s0>Sensibilité</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="ENG"><s0>Sensitivity</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="SPA"><s0>Sensibilidad</s0>
<s5>01</s5>
</fC03>
<fC03 i1="02" i2="X" l="FRE"><s0>Antiviral</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Antiviral</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="SPA"><s0>Antiviral</s0>
<s5>02</s5>
</fC03>
<fC03 i1="03" i2="X" l="FRE"><s0>Médicament</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="ENG"><s0>Drug</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA"><s0>Medicamento</s0>
<s5>03</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Mutation</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Mutation</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Mutación</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Exo-α-sialidase</s0>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Exo-α-sialidase</s0>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Exo-α-sialidase</s0>
<s2>FE</s2>
<s5>05</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE"><s0>Dynamique moléculaire</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Molecular dynamics</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Dinámica molecular</s0>
<s5>06</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Simulation</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>Simulation</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA"><s0>Simulación</s0>
<s5>07</s5>
</fC03>
<fC03 i1="08" i2="X" l="FRE"><s0>Energie libre</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG"><s0>Free energy</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Energía libre</s0>
<s5>08</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE"><s0>Calcul</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG"><s0>Calculation</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA"><s0>Cálculo</s0>
<s5>09</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE"><s0>Grippe</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="ENG"><s0>Influenza</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA"><s0>Gripe</s0>
<s5>10</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE"><s0>Inhibiteur neuraminidase</s0>
<s2>FR</s2>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG"><s0>Neuraminidase inhibitor</s0>
<s2>FR</s2>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA"><s0>Inhibidor neuraminidas</s0>
<s2>FR</s2>
<s5>11</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE"><s0>Résistance traitement</s0>
<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="ENG"><s0>Treatment resistance</s0>
<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="SPA"><s0>Resistencia tratamiento</s0>
<s5>12</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE"><s0>Influenzavirus A(H1N1)</s0>
<s4>INC</s4>
<s5>86</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE"><s0>Virus grippal A(H1N1)</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC03 i1="14" i2="X" l="ENG"><s0>Influenza A (H1N1)</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Glycosidases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Glycosidases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Glycosidases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Glycosylases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Glycosylases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Glycosylases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Hydrolases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Hydrolases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Hydrolases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Enzima</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Virose</s0>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Viral disease</s0>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Virosis</s0>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Infection</s0>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Infection</s0>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Infección</s0>
</fC07>
<fN21><s1>006</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
</standard>
<server><NO>PASCAL 14-0009028 INIST</NO>
<ET>Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations</ET>
<AU>PEICHEN PAN; LIN LI; YOUYONG LI; DAN LI; TINGJUN HOU</AU>
<AF>Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University/Suzhou, Jiangsu 215123/Chine (1 aut., 2 aut., 3 aut., 5 aut.); College of Pharmaceutical Sciences, Zhejiang University/Hangzhou, Zhejiang 310058/Chine (4 aut., 5 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Antiviral research; ISSN 0166-3542; Coden ARSRDR; Royaume-Uni; Da. 2013; Vol. 100; No. 2; Pp. 356-364; Bibl. 1 p.1/2</SO>
<LA>Anglais</LA>
<EA>Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV > PRV > OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance.</EA>
<CC>002B02S05; 002B05C02C</CC>
<FD>Sensibilité; Antiviral; Médicament; Mutation; Exo-α-sialidase; Dynamique moléculaire; Simulation; Energie libre; Calcul; Grippe; Inhibiteur neuraminidase; Résistance traitement; Influenzavirus A(H1N1); Virus grippal A(H1N1)</FD>
<FG>Glycosidases; Glycosylases; Hydrolases; Enzyme; Virose; Infection</FG>
<ED>Sensitivity; Antiviral; Drug; Mutation; Exo-α-sialidase; Molecular dynamics; Simulation; Free energy; Calculation; Influenza; Neuraminidase inhibitor; Treatment resistance; Influenza A (H1N1)</ED>
<EG>Glycosidases; Glycosylases; Hydrolases; Enzyme; Viral disease; Infection</EG>
<SD>Sensibilidad; Antiviral; Medicamento; Mutación; Exo-α-sialidase; Dinámica molecular; Simulación; Energía libre; Cálculo; Gripe; Inhibidor neuraminidas; Resistencia tratamiento</SD>
<LO>INIST-18839.354000507415610090</LO>
<ID>14-0009028</ID>
</server>
</inist>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Sante/explor/PandemieGrippaleV1/Data/PascalFrancis/Corpus

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000173 | SxmlIndent | more

HfdSelect -h $EXPLOR_AREA/Data/PascalFrancis/Corpus/biblio.hfd -nk 000173 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    PandemieGrippaleV1
   |flux=    PascalFrancis
   |étape=   Corpus
   |type=    RBID
   |clé=     Pascal:14-0009028
   |texte=   Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations
}}

This area was generated with Dilib version V0.6.34.
Data generation: Wed Jun 10 11:04:28 2020. Site generation: Sun Mar 28 09:10:28 2021

	Serveur d'exploration sur les pandémies grippales
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.

Serveur d'exploration sur les pandémies grippales

Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations

Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations

Source :

Descripteurs français

English descriptors

Abstract

Notice en format standard (ISO 2709)

Format Inist (serveur)

Links to Exploration step

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri