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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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Related in: MedlinePlus

The molecular structures for the five small molecules: (a) oseltamivir carboxylate; (b) quercetin; (c) baicalein; (d) chlorogenic acid; (e) oleanolic acid.
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fig1: The molecular structures for the five small molecules: (a) oseltamivir carboxylate; (b) quercetin; (c) baicalein; (d) chlorogenic acid; (e) oleanolic acid.

Mentions: In this study, five small molecules including oseltamivir carboxylate (Figure 1(a)), quercetin (Figure 1(b)), baicalein (Figure 1(c)), chlorogenic acid (Figure 1(d)), and oleanolic acid (Figure 1(e)) were employed for docking with neuraminidase to explore the potential inhibitor. Previously, it was observed that the oseltamivir phosphate is the prodrug without antivirus activity while its product of metabolism oseltamivir carboxylate is active [30]. Thus, in this study, the oseltamivir carboxylate was employed for molecular docking. The chemoinformatic analyses were performed with the FAF-Drugs3 software [29] to further understand the properties of the small molecules. Since the hydrogen bonds (H-bonds) were critical for the interactions and binding affinity between the protein and small molecules, we analyzed the H-bond donors and acceptors of these small molecules. It was observed that oseltamivir carboxylate and quercetin, chlorogenic acid and baicalein have five and six H-bond donors, respectively, while oleanolic acid has two (Table 1). Baicalein has 11 H-bond acceptors, while chlorogenic acid, quercetin, oseltamivir carboxylate, and oleanolic acid have 9, 7, 6, and 3 H-bond acceptors, respectively (Table 1). These results showed that quercetin, chlorogenic acid, oleanolic acid, and baicalein had the potential to form H-bonds with proteins. Furthermore, the potential toxicities and promiscuities were analyzed by the FAF-Drugs3 software [29]. It was observed that baicalein, chlorogenic acid, quercetin, and oseltamivir carboxylate have low toxicities and promiscuities according to the threshold of log⁡⁡P < 3 and tPSA > 75 (Table 1). Furthermore, oleanolic acid has the log⁡⁡P of 7.49 and tPSA of 60.36 (Table 1). However, oleanolic acid was proved as a drug for human liver disorders treatment [31]. Thus, it seemed that four small molecules had limited toxicities and promiscuities and were proper for further drug development.


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 molecular structures for the five small molecules: (a) oseltamivir carboxylate; (b) quercetin; (c) baicalein; (d) chlorogenic acid; (e) oleanolic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The molecular structures for the five small molecules: (a) oseltamivir carboxylate; (b) quercetin; (c) baicalein; (d) chlorogenic acid; (e) oleanolic acid.
Mentions: In this study, five small molecules including oseltamivir carboxylate (Figure 1(a)), quercetin (Figure 1(b)), baicalein (Figure 1(c)), chlorogenic acid (Figure 1(d)), and oleanolic acid (Figure 1(e)) were employed for docking with neuraminidase to explore the potential inhibitor. Previously, it was observed that the oseltamivir phosphate is the prodrug without antivirus activity while its product of metabolism oseltamivir carboxylate is active [30]. Thus, in this study, the oseltamivir carboxylate was employed for molecular docking. The chemoinformatic analyses were performed with the FAF-Drugs3 software [29] to further understand the properties of the small molecules. Since the hydrogen bonds (H-bonds) were critical for the interactions and binding affinity between the protein and small molecules, we analyzed the H-bond donors and acceptors of these small molecules. It was observed that oseltamivir carboxylate and quercetin, chlorogenic acid and baicalein have five and six H-bond donors, respectively, while oleanolic acid has two (Table 1). Baicalein has 11 H-bond acceptors, while chlorogenic acid, quercetin, oseltamivir carboxylate, and oleanolic acid have 9, 7, 6, and 3 H-bond acceptors, respectively (Table 1). These results showed that quercetin, chlorogenic acid, oleanolic acid, and baicalein had the potential to form H-bonds with proteins. Furthermore, the potential toxicities and promiscuities were analyzed by the FAF-Drugs3 software [29]. It was observed that baicalein, chlorogenic acid, quercetin, and oseltamivir carboxylate have low toxicities and promiscuities according to the threshold of log⁡⁡P < 3 and tPSA > 75 (Table 1). Furthermore, oleanolic acid has the log⁡⁡P of 7.49 and tPSA of 60.36 (Table 1). However, oleanolic acid was proved as a drug for human liver disorders treatment [31]. Thus, it seemed that four small molecules had limited toxicities and promiscuities and were proper for further drug development.

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