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 : 000174Insights 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 HOUSource :
- Antiviral research [ 0166-3542 ] ; 2013.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
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.
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Format Inist (serveur)
NO : | PASCAL 14-0009028 INIST |
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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 |
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Pascal:14-0009028Le document en format XML
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<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>
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<fC03 i1="14" i2="X" l="FRE"><s0>Virus grippal A(H1N1)</s0>
<s4>CD</s4>
<s5>96</s5>
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<s4>CD</s4>
<s5>96</s5>
</fC03>
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<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>
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<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>
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