Molecular Dynamics Study on Laninamivir Inhibiting Neuraminidases of H5N1 and pH1N1 Influenza a Viruses

Viral influenza A subtypes H5N1 and pandemic H1N1 (pH1N1) have worldwide emerged and transmitted. The most common anti-influenza drug for treatment of both seasonal and pandemic influenza viruses is oseltamivir that nowadays becomes resistance to influenza neuraminidase. The novel long-acting drug, laninamivir, was discovered for treatment of the patients infected with influenza B and influenza A viruses. In the present study, laninamivir complexed with wild-type strain of both H5N1 and pH1N1 viruses were comparatively determined the structures and drug-target interactions by means of molecular dynamics (MD) simulations. The results show that the hydrogen bonding interactions formed between laninamivir and its binding residues are likely similar for the two systems. Additionally, the presence of intermolecular interactions from laninamivir to the residues in the binding pocket is established through their side chains in accordance with hydrogen bond interactions.

Authors:

• A. Meeprasert
• W. Khuntawee
• S. Hannongbua
• T. Rungrotmongkol

Keywords:

• Laninamivir
• neuraminidase
• H5N1
• pandemic H1N1
• wild-type
• MD simulation

References:

[1] Collins, P.J., Haire, L.F., Lin, Y.P., Liu, J., Russell, R.J., Walker, P.A.,
Skehel, J.J., Martin, S.R., Hay, A.J. and Gamblin, S.J., "Crystal structures of oseltamivir-resistant influenza virus neuraminidase
mutants," Nature, vol. 453, pp. 1258-61, 2008.
[2] Neumann, G., Noda, T. and Kawaoka, Y., "Emergence and pandemic
potential of swine-origin H1N1 influenza virus," Nature, vol. 459, pp. 931-9, 2009.
[3] Yamashita, M., Tomozawa, T., Kakuta, M., Tokumitsu, A., Nasu, H. and
Kubo, S., "CS-8958, a prodrug of the new neuraminidase inhibitor R-
125489, shows long-acting anti-influenza virus activity," Antimicrobial
Agents and Chemotherapy, vol. 53, pp. 186-92, 2009.
[4] Kubo, S., Tomozawa, T., Kakuta, M., Tokumitsu, A. and Yamashita, M.,
"Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor,
shows superior anti-influenza virus activity after a single
administration," Antimicrobial Agents and Chemotherapy, vol. 54, pp.
1256-64, 2010.
[5] Sugaya, N. and Ohashi, Y., "Long-Acting Neuraminidase Inhibitor
Laninamivir Octanoate (CS-8958) versus Oseltamivir as Treatment for
Children with Influenza Virus Infection," Antimicrobial Agents and
Chemotherapy, vol. 54, pp. 2575-82, 2010.
[6] Bright, R.A., Shay, D.K., Shu, B., Cox, N.J. and Klimov, A.I.,
"Adamantane Resistance Among Influenza A Viruses Isolated Early
During the 2005-2006 Influenza Season in the United States," JAMA:
The Journal of the American Medical Association, vol. 295, pp. 891-4, 2006.
[7] Deyde, V.M., Xu, X., Bright, R.A., Shaw, M., Smith, C.B., Zhang, Y.,
Shu, Y., Gubareva, L.V., Cox, N.J. and Klimov, A.I., "Surveillance of
Resistance to Adamantanes among Influenza A(H3N2) and A(H1N1) Viruses Isolated Worldwide," Journal of Infectious Diseases, vol. 196,
pp. 249-57, 2007.
[8] Yamashita, M., "Laninamivir and its prodrug, CS-8958: long-acting
neuraminidase inhibitors for the treatment of influenza," Antiviral
Chemistry and Chemotherapy, vol. 21, pp. 71-84, 2010.
[9] Nguyen, H.T., Sheu, T.G., Mishin, V.P., Klimov, A.I. and Gubareva,
L.V., "Assessment of pandemic and seasonal influenza A (H1N1) virus
susceptibility to neuraminidase inhibitors in three enzyme activity
inhibition assays," Antimicrobial Agents and Chemotherapy, vol. 54, pp.
3671-7, 2010.
[10] Case, D.A., Cheatham, T.E., Darden, T., Gohlke, H., Luo, R., Merz,
K.M., Onufriev, A., Simmerling, C., Wang, B. and Woods, R.J., "The
Amber biomolecular simulation programs," Journal of Computational
Chemistry, vol. 26, pp. 1668-88, 2005.
[11] Gohlke, H. and Case, D.A., "Converging free energy estimates: MMPB(
GB)SA studies on the protein-protein complex Ras-Raf," Journal of
Computational Chemistry, vol. 25, pp. 238-50, 2004.
[12] Malaisree, M., Rungrotmongkol, T., Decha, P., Intharathep, P.,
Aruksakunwong, O. and Hannongbua, S., "Understanding of known
drug-target interactions in the catalytic pocket of neuraminidase subtype
N1," Proteins: Structure, Function, and Bioinformatics, vol. 71, pp. 1908-18, 2008.
[13] Pan, D., Sun, H., Bai, C., Shen, Y., Jin, N., Liu, H. and Yao, X., "Prediction of zanamivir efficiency over the possible 2009 influenza A
(H1N1) mutants by multiple molecular dynamics simulations and free
energy calculations," Journal of Molecular Modeling, vol. 17, pp. 2465-73, 2011.
[14] Le, L., Lee, E., Schulten, K. and Truong, T.N., "Molecular modeling of
swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1
neuraminidases bound to tamiflu and relenza," PLOS Currents: Influenza, vol. 1, pp. RRN1015, 2009.
[15] Udommaneethanakit, T., Rungrotmongkol, T., Bren, U., Frecer, V. and
Stanislav, M., "Dynamic behavior of avian influenza A virus neuraminidase subtype H5N1 in complex with oseltamivir, zanamivir, peramivir, and their phosphonate analogues," Journal of Chemical
Information and Modeling, vol. 49, pp. 2323-32, 2009.
[16] Bonnet, P. and Bryce, R.A., "Molecular dynamics and free energy
analysis of neuraminidase-ligand interactions," Protein Science, vol. 13,
pp. 946-57, 2004.
[17] Rungrotmongkol, T., Frecer, V., De-Eknamkul, W., Hannongbua, S. and
Miertus, S., "Design of oseltamivir analogs inhibiting neuraminidase of
avian influenza virus H5N1," Antiviral Research, vol. 82, pp. 51-8, 2009.
[18] Rungrotmongkol, T., Udommaneethanakit, T., Frecer, V. and Miertus, S.,
"Combinatorial design of avian influenza neuraminidase inhibitors
containing pyrrolidine core with a reduced susceptibility to viral drug resistance," Comb Chem High Throughput Screen, vol. 13, pp. 268-77,
2010.