Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: a homology modeling and flexible docking study
Abstract
In the context of the recent pandemic threat by the worldwide spread of H5N1 avian influenza, novel insights into the mechanism of ligand binding and interaction between various inhibitors (zanamivir - ZMV, oseltamivir - OTV, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid - DANA, peramivir - PMV) and neuraminidases (NA) are of vital importance for the structure-based design of new anti-viral drugs. To address this issue, three-dimensional models of H5N1-NA and N9-NA were generated by homology modeling. Traditional residues within the active site throughout the family of NA protein structures were found to be highly conserved in H5N1-NA. A subtle variation between lipophilic and hydrophilic environments in H5N1-NA with respect to N9-NA was observed, thus shedding more light on the high resistance of some H5N1 strains to various NA inhibitors. Based on these models, an ArgusLab4/AScore flexible docking study was performed. The conformational differences between OTV bound to H5N1-NA and OT...V bound to N9-NA were structurally identified and quantified. A slight difference of less than 1 kcal mol(-1) between the OTV-N9 and OTV-N1 binding free energies is in agreement with the experimentally predicted free energy difference. The conformational differences between ZMV and OTV bound to either H5N1-NA or N9-NA were structurally identified. The binding free energies of the ZMV complexes, being slightly higher than those of OTV, are not in agreement with what was previously proposed using homology modeling. The differences between-ZMV and OTV are suggested to be ascribed to the presence/absence of Asn 166 in the active cavity of ZMV/OTV in H5N1-NA, and to the presence/absence of Ser165 in the binding site of ZMV/OTV in N9-NA. The charge distribution was evaluated using the semi-empirical AMI method. The trends of the AMI charges of the ZMV and OTV side chains in the complexes deviate from those previously reported.
Keywords:
zanamivir / oseltamivir / homology modeling / H5N1 avian influenza virus neuraminidase / Argus Lab 4.0 dockingSource:
Journal of the Serbian Chemical Society, 2009, 74, 1, 1-13Publisher:
- Srpsko hemijsko društvo, Beograd
DOI: 10.2298/JSC0901001M
ISSN: 0352-5139
WoS: 000263036400001
Scopus: 2-s2.0-68849094171
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Institution/Community
Institut za tehnologiju nuklearnih i drugih mineralnih sirovinaTY - JOUR AU - Mihajlović, Marija AU - Mitrašinović, Petar M. PY - 2009 UR - https://ritnms.itnms.ac.rs/handle/123456789/153 AB - In the context of the recent pandemic threat by the worldwide spread of H5N1 avian influenza, novel insights into the mechanism of ligand binding and interaction between various inhibitors (zanamivir - ZMV, oseltamivir - OTV, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid - DANA, peramivir - PMV) and neuraminidases (NA) are of vital importance for the structure-based design of new anti-viral drugs. To address this issue, three-dimensional models of H5N1-NA and N9-NA were generated by homology modeling. Traditional residues within the active site throughout the family of NA protein structures were found to be highly conserved in H5N1-NA. A subtle variation between lipophilic and hydrophilic environments in H5N1-NA with respect to N9-NA was observed, thus shedding more light on the high resistance of some H5N1 strains to various NA inhibitors. Based on these models, an ArgusLab4/AScore flexible docking study was performed. The conformational differences between OTV bound to H5N1-NA and OTV bound to N9-NA were structurally identified and quantified. A slight difference of less than 1 kcal mol(-1) between the OTV-N9 and OTV-N1 binding free energies is in agreement with the experimentally predicted free energy difference. The conformational differences between ZMV and OTV bound to either H5N1-NA or N9-NA were structurally identified. The binding free energies of the ZMV complexes, being slightly higher than those of OTV, are not in agreement with what was previously proposed using homology modeling. The differences between-ZMV and OTV are suggested to be ascribed to the presence/absence of Asn 166 in the active cavity of ZMV/OTV in H5N1-NA, and to the presence/absence of Ser165 in the binding site of ZMV/OTV in N9-NA. The charge distribution was evaluated using the semi-empirical AMI method. The trends of the AMI charges of the ZMV and OTV side chains in the complexes deviate from those previously reported. PB - Srpsko hemijsko društvo, Beograd T2 - Journal of the Serbian Chemical Society T1 - Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: a homology modeling and flexible docking study EP - 13 IS - 1 SP - 1 VL - 74 DO - 10.2298/JSC0901001M UR - conv_555 ER -
@article{ author = "Mihajlović, Marija and Mitrašinović, Petar M.", year = "2009", abstract = "In the context of the recent pandemic threat by the worldwide spread of H5N1 avian influenza, novel insights into the mechanism of ligand binding and interaction between various inhibitors (zanamivir - ZMV, oseltamivir - OTV, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid - DANA, peramivir - PMV) and neuraminidases (NA) are of vital importance for the structure-based design of new anti-viral drugs. To address this issue, three-dimensional models of H5N1-NA and N9-NA were generated by homology modeling. Traditional residues within the active site throughout the family of NA protein structures were found to be highly conserved in H5N1-NA. A subtle variation between lipophilic and hydrophilic environments in H5N1-NA with respect to N9-NA was observed, thus shedding more light on the high resistance of some H5N1 strains to various NA inhibitors. Based on these models, an ArgusLab4/AScore flexible docking study was performed. The conformational differences between OTV bound to H5N1-NA and OTV bound to N9-NA were structurally identified and quantified. A slight difference of less than 1 kcal mol(-1) between the OTV-N9 and OTV-N1 binding free energies is in agreement with the experimentally predicted free energy difference. The conformational differences between ZMV and OTV bound to either H5N1-NA or N9-NA were structurally identified. The binding free energies of the ZMV complexes, being slightly higher than those of OTV, are not in agreement with what was previously proposed using homology modeling. The differences between-ZMV and OTV are suggested to be ascribed to the presence/absence of Asn 166 in the active cavity of ZMV/OTV in H5N1-NA, and to the presence/absence of Ser165 in the binding site of ZMV/OTV in N9-NA. The charge distribution was evaluated using the semi-empirical AMI method. The trends of the AMI charges of the ZMV and OTV side chains in the complexes deviate from those previously reported.", publisher = "Srpsko hemijsko društvo, Beograd", journal = "Journal of the Serbian Chemical Society", title = "Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: a homology modeling and flexible docking study", pages = "13-1", number = "1", volume = "74", doi = "10.2298/JSC0901001M", url = "conv_555" }
Mihajlović, M.,& Mitrašinović, P. M.. (2009). Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: a homology modeling and flexible docking study. in Journal of the Serbian Chemical Society Srpsko hemijsko društvo, Beograd., 74(1), 1-13. https://doi.org/10.2298/JSC0901001M conv_555
Mihajlović M, Mitrašinović PM. Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: a homology modeling and flexible docking study. in Journal of the Serbian Chemical Society. 2009;74(1):1-13. doi:10.2298/JSC0901001M conv_555 .
Mihajlović, Marija, Mitrašinović, Petar M., "Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: a homology modeling and flexible docking study" in Journal of the Serbian Chemical Society, 74, no. 1 (2009):1-13, https://doi.org/10.2298/JSC0901001M ., conv_555 .