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In silico identification of the potential drug resistance sites over 2009 influenza A (H1N1) virus neuraminidase.
Mol Pharm. 2010 Jun 07; 7(3):894-904.MP

Abstract

The outbreak and high speed global spread of the new strain of influenza A (H1N1) virus in 2009 poses a serious threat to the general population and governments. At present, the most effective drugs for the treatment of 2009 influenza A (H1N1) virus are neuraminidase inhibitors: mainly oseltamivir and zanamivir. The use of these two inhibitors will undoubtedly increase, and therefore it is more likely that drug-resistant influenza strains will arise. The identification of the potential resistance sites for these drugs in advance and the understanding of corresponding molecular basis to cause drug resistance are no doubt very important to fight against the new resistant influenza strains. In this study, first, the complexes of neuraminidase with the substrate sialic acid and two inhibitors oseltamivir and zanamivir were obtained by fitting them to the 3D structure of 2009 influenza A (H1N1) neuraminidase obtained by homology modeling. By using these complexes as the initial structures, molecular dynamics simulation and molecular mechanics generalized Born surface area (MM-GBSA) calculations were performed to identify the residues with significant contribution to the binding of substrate and inhibitors. By analyzing the difference of interaction profiles of substrate and inhibitors, the potential drug resistance sites for two inhibitors were identified. Parts of the identified sites have been verified to confer resistance to oseltamivir and zanamivir for influenza virus of the past flu epidemic. The identified potential resistance sites in this study will be useful for the development of new effective drugs against the drug resistance and avoid the situation of having no effective drugs to treat new mutant influenza strains.

Authors+Show Affiliations

School of Pharmacy, Department of Chemistry, and Key Lab of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, China. hxliu@lzu.edu.cnNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20420444

Citation

Liu, Huanxiang, et al. "In Silico Identification of the Potential Drug Resistance Sites Over 2009 Influenza a (H1N1) Virus Neuraminidase." Molecular Pharmaceutics, vol. 7, no. 3, 2010, pp. 894-904.
Liu H, Yao X, Wang C, et al. In silico identification of the potential drug resistance sites over 2009 influenza A (H1N1) virus neuraminidase. Mol Pharm. 2010;7(3):894-904.
Liu, H., Yao, X., Wang, C., & Han, J. (2010). In silico identification of the potential drug resistance sites over 2009 influenza A (H1N1) virus neuraminidase. Molecular Pharmaceutics, 7(3), 894-904. https://doi.org/10.1021/mp100041b
Liu H, et al. In Silico Identification of the Potential Drug Resistance Sites Over 2009 Influenza a (H1N1) Virus Neuraminidase. Mol Pharm. 2010 Jun 7;7(3):894-904. PubMed PMID: 20420444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In silico identification of the potential drug resistance sites over 2009 influenza A (H1N1) virus neuraminidase. AU - Liu,Huanxiang, AU - Yao,Xiaojun, AU - Wang,Chengqi, AU - Han,Jian, PY - 2010/4/28/entrez PY - 2010/4/28/pubmed PY - 2010/9/8/medline SP - 894 EP - 904 JF - Molecular pharmaceutics JO - Mol. Pharm. VL - 7 IS - 3 N2 - The outbreak and high speed global spread of the new strain of influenza A (H1N1) virus in 2009 poses a serious threat to the general population and governments. At present, the most effective drugs for the treatment of 2009 influenza A (H1N1) virus are neuraminidase inhibitors: mainly oseltamivir and zanamivir. The use of these two inhibitors will undoubtedly increase, and therefore it is more likely that drug-resistant influenza strains will arise. The identification of the potential resistance sites for these drugs in advance and the understanding of corresponding molecular basis to cause drug resistance are no doubt very important to fight against the new resistant influenza strains. In this study, first, the complexes of neuraminidase with the substrate sialic acid and two inhibitors oseltamivir and zanamivir were obtained by fitting them to the 3D structure of 2009 influenza A (H1N1) neuraminidase obtained by homology modeling. By using these complexes as the initial structures, molecular dynamics simulation and molecular mechanics generalized Born surface area (MM-GBSA) calculations were performed to identify the residues with significant contribution to the binding of substrate and inhibitors. By analyzing the difference of interaction profiles of substrate and inhibitors, the potential drug resistance sites for two inhibitors were identified. Parts of the identified sites have been verified to confer resistance to oseltamivir and zanamivir for influenza virus of the past flu epidemic. The identified potential resistance sites in this study will be useful for the development of new effective drugs against the drug resistance and avoid the situation of having no effective drugs to treat new mutant influenza strains. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/20420444/In_silico_identification_of_the_potential_drug_resistance_sites_over_2009_influenza_A__H1N1__virus_neuraminidase_ L2 - https://dx.doi.org/10.1021/mp100041b DB - PRIME DP - Unbound Medicine ER -