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Molecular docking of potential inhibitors for influenza H7N9.

Liu Z, Zhao J, Li W, Wang X, Xu J, Xie J, Tao K, Shen L, Zhang R - Comput Math Methods Med (2015)

Bottom Line: In this regard, it is urgent to develop new effective anti-H7N9 drug.Further analyses showed that R294K mutation in neuraminidase could remarkably decrease the binding energies for oseltamivir, while other small molecules showed stable binding abilities with mutated neuraminidase.Taken together, the molecular docking studies identified four potential inhibitors for neuraminidase of H7N9, which might be effective for the drug-resistant mutants.

View Article: PubMed Central - PubMed

Affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, China.

ABSTRACT
As a new strain of virus emerged in 2013, avian influenza A (H7N9) virus is a threat to the public health, due to its high lethality and pathogenicity. Furthermore, H7N9 has already generated various mutations such as neuraminidase R294K mutation which could make the anti-influenza oseltamivir less effective or ineffective. In this regard, it is urgent to develop new effective anti-H7N9 drug. In this study, we used the general H7N9 neuraminidase and oseltamivir-resistant influenza virus neuraminidase as the acceptors and employed the small molecules including quercetin, chlorogenic acid, baicalein, and oleanolic acid as the donors to perform the molecular docking for exploring the binding abilities between these small molecules and neuraminidase. The results showed that quercetin, chlorogenic acid, oleanolic acid, and baicalein present oseltamivir-comparable high binding potentials with neuraminidase. Further analyses showed that R294K mutation in neuraminidase could remarkably decrease the binding energies for oseltamivir, while other small molecules showed stable binding abilities with mutated neuraminidase. Taken together, the molecular docking studies identified four potential inhibitors for neuraminidase of H7N9, which might be effective for the drug-resistant mutants.

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The local structure of the docking complexes for small molecules and neuraminidase: (a) chlorogenic acid and (b) oleanolic acid.
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fig4: The local structure of the docking complexes for small molecules and neuraminidase: (a) chlorogenic acid and (b) oleanolic acid.

Mentions: To further dissect the interaction between neuraminidase and the small molecules, the structures in complex derived from the best dock results with neuraminidase for oseltamivir carboxylate (Figure 3(a)), quercetin (Figure 3(b)), chlorogenic acid (Figure 4(a)), oleanolic acid (Figure 4(b)), and baicalein (Figure 5) derived from molecular docking were shown. From the molecule docking among A/Anhui/1/2013 neuraminidase and small molecules, it was observed that there were 18 H-bonds in the neuraminidase-chlorogenic acid complex (Figure 4(a)), while quercetin (Figure 3(b)) has 14 H-bonds with neuraminidase. Oseltamivir carboxylate (Figure 3(a)) and baicalein (Figure 5) both have 12 H-bonds with neuraminidase, while oleanolic acid (Figure 4(b)) has 5. The H-bond residues for neuraminidase from A/Anhui/1/2013 and A/Shanghai/1/2013 were provided in Tables 4 and 5, respectively. These results indicated that chlorogenic acid, quercetin, and baicalein could intensively bind neuraminidase through H-bonds. For A/Shanghai/1/2013 neuraminidase, chlorogenic acid could form 17 H-bonds (Figure 4(a)), which indicated that chlorogenic acid has high potential of neuraminidase inhibition. It was interesting that the H-bonds for baicalein (Figure 5) and oleanolic acid (Figure 4(b)) were increased to 15 and 8 for A/Shanghai/1/2013 neuraminidase compared to those from A/Anhui/1/2013, while there were 9 and 11 H-bonds for oseltamivir carboxylate (Figure 3(a)) and quercetin (Figure 3(b)), respectively. These results indicated that the oseltamivir resistance caused by R294K mutation for neuraminidase in A/Shanghai/1/2013 might be generated from the H-bond loss, while other molecules might overcome the resistance. Furthermore, other known inhibitors of neuraminidase including zanamivir, peramivir, and laninamivir had similar structures and presented similar inhibition abilities for neuraminidase from A/Anhui/1/2013 [10]. However, they also showed significantly decreased inhibition for A/Shanghai/1/2013 [10]. Since the small molecules including quercetin, chlorogenic acid, oleanolic acid, and baicalein had longer structures and there was considerable room for improvements, we anticipated that they had great potential to overcome the drug resistance of H7N9 mutant.


Molecular docking of potential inhibitors for influenza H7N9.

Liu Z, Zhao J, Li W, Wang X, Xu J, Xie J, Tao K, Shen L, Zhang R - Comput Math Methods Med (2015)

The local structure of the docking complexes for small molecules and neuraminidase: (a) chlorogenic acid and (b) oleanolic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4377397&req=5

fig4: The local structure of the docking complexes for small molecules and neuraminidase: (a) chlorogenic acid and (b) oleanolic acid.
Mentions: To further dissect the interaction between neuraminidase and the small molecules, the structures in complex derived from the best dock results with neuraminidase for oseltamivir carboxylate (Figure 3(a)), quercetin (Figure 3(b)), chlorogenic acid (Figure 4(a)), oleanolic acid (Figure 4(b)), and baicalein (Figure 5) derived from molecular docking were shown. From the molecule docking among A/Anhui/1/2013 neuraminidase and small molecules, it was observed that there were 18 H-bonds in the neuraminidase-chlorogenic acid complex (Figure 4(a)), while quercetin (Figure 3(b)) has 14 H-bonds with neuraminidase. Oseltamivir carboxylate (Figure 3(a)) and baicalein (Figure 5) both have 12 H-bonds with neuraminidase, while oleanolic acid (Figure 4(b)) has 5. The H-bond residues for neuraminidase from A/Anhui/1/2013 and A/Shanghai/1/2013 were provided in Tables 4 and 5, respectively. These results indicated that chlorogenic acid, quercetin, and baicalein could intensively bind neuraminidase through H-bonds. For A/Shanghai/1/2013 neuraminidase, chlorogenic acid could form 17 H-bonds (Figure 4(a)), which indicated that chlorogenic acid has high potential of neuraminidase inhibition. It was interesting that the H-bonds for baicalein (Figure 5) and oleanolic acid (Figure 4(b)) were increased to 15 and 8 for A/Shanghai/1/2013 neuraminidase compared to those from A/Anhui/1/2013, while there were 9 and 11 H-bonds for oseltamivir carboxylate (Figure 3(a)) and quercetin (Figure 3(b)), respectively. These results indicated that the oseltamivir resistance caused by R294K mutation for neuraminidase in A/Shanghai/1/2013 might be generated from the H-bond loss, while other molecules might overcome the resistance. Furthermore, other known inhibitors of neuraminidase including zanamivir, peramivir, and laninamivir had similar structures and presented similar inhibition abilities for neuraminidase from A/Anhui/1/2013 [10]. However, they also showed significantly decreased inhibition for A/Shanghai/1/2013 [10]. Since the small molecules including quercetin, chlorogenic acid, oleanolic acid, and baicalein had longer structures and there was considerable room for improvements, we anticipated that they had great potential to overcome the drug resistance of H7N9 mutant.

Bottom Line: In this regard, it is urgent to develop new effective anti-H7N9 drug.Further analyses showed that R294K mutation in neuraminidase could remarkably decrease the binding energies for oseltamivir, while other small molecules showed stable binding abilities with mutated neuraminidase.Taken together, the molecular docking studies identified four potential inhibitors for neuraminidase of H7N9, which might be effective for the drug-resistant mutants.

View Article: PubMed Central - PubMed

Affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, China.

ABSTRACT
As a new strain of virus emerged in 2013, avian influenza A (H7N9) virus is a threat to the public health, due to its high lethality and pathogenicity. Furthermore, H7N9 has already generated various mutations such as neuraminidase R294K mutation which could make the anti-influenza oseltamivir less effective or ineffective. In this regard, it is urgent to develop new effective anti-H7N9 drug. In this study, we used the general H7N9 neuraminidase and oseltamivir-resistant influenza virus neuraminidase as the acceptors and employed the small molecules including quercetin, chlorogenic acid, baicalein, and oleanolic acid as the donors to perform the molecular docking for exploring the binding abilities between these small molecules and neuraminidase. The results showed that quercetin, chlorogenic acid, oleanolic acid, and baicalein present oseltamivir-comparable high binding potentials with neuraminidase. Further analyses showed that R294K mutation in neuraminidase could remarkably decrease the binding energies for oseltamivir, while other small molecules showed stable binding abilities with mutated neuraminidase. Taken together, the molecular docking studies identified four potential inhibitors for neuraminidase of H7N9, which might be effective for the drug-resistant mutants.

Show MeSH
Related in: MedlinePlus