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Tsinghua Science and Technology 2015, 20(5): 431-440 https://doi.org/10.1109/TST.2015.7297742
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Designing Cyclopentapeptide Inhibitor of Neuraminidase H5N1 Virus Through Molecular and Pharmacology Simulations

Show Author's Information Usman Sumo Friend Tambunan( ),  Arli Aditya Parikesit,  Yossy Carolina Unadi,  Djati Kerami
Bioinformatics Research Group, Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Depok 16424, Indonesia.
Mathematics Computation Research Group, Department of Mathematics, Faculty of Mathematics and Science, University of Indonesia, Depok 16424, Indonesia.
Keywords:
molecular dynamics, H5N1, neuraminidase, cyclical pentapeptide, molecular docking
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Tambunan USF, Parikesit AA, Unadi YC, et al. Designing Cyclopentapeptide Inhibitor of Neuraminidase H5N1 Virus Through Molecular and Pharmacology Simulations. Tsinghua Science and Technology, 2015, 20(5): 431-440. https://doi.org/10.1109/TST.2015.7297742
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Abstract Full text About this article

Highly Pathogenic Avian Influenza (HPAI) H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase (NA) has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy ( Δ⁢Gbinding). ADME-Tox prediction assay was conducted on the selected ligands. Intra- and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein: CLDRC and CIWRC. These two ligands have Δ⁢Gbinding values of -40.5854 and -39.9721 kcal/mol (1 kcal/mol = 4.18 kJ/mol). These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312 K. At the end, both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.


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About this article

Designing Cyclopentapeptide Inhibitor of Neuraminidase H5N1 Virus Through Molecular and Pharmacology Simulations

Show Author's information Usman Sumo Friend Tambunan( ), Arli Aditya Parikesit, Yossy Carolina Unadi, Djati Kerami
Bioinformatics Research Group, Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Depok 16424, Indonesia.
Mathematics Computation Research Group, Department of Mathematics, Faculty of Mathematics and Science, University of Indonesia, Depok 16424, Indonesia.

Abstract

Highly Pathogenic Avian Influenza (HPAI) H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase (NA) has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy ( Δ⁢Gbinding). ADME-Tox prediction assay was conducted on the selected ligands. Intra- and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein: CLDRC and CIWRC. These two ligands have Δ⁢Gbinding values of -40.5854 and -39.9721 kcal/mol (1 kcal/mol = 4.18 kJ/mol). These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312 K. At the end, both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.

Keywords: molecular dynamics, H5N1, neuraminidase, cyclical pentapeptide, molecular docking

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Received: 03 March 2015
Accepted: 11 August 2015
Published: 13 October 2015
Issue date: October 2015

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Acknowledgements

The authors would like to thank Hibah PUPT BOPTN Ditjen Dikti 2015 No. 0528/UN2.R12/HKP.05.00/2015, for supporting this research. Usman Sumo Friend Tambunan supervised this research, while Yossy Gunadi worked on the technical details. Usman Sumo Friend Tambunan and Arli Aditya Parikesit wrote the manuscript. Arli Aditya Parikesit re-verified the data. Djati Kerami also gave critical suggestion for improving the methodology. We also extend our heartfelt gratitude to Niken Widiyanti for proof reading the manuscript and Muhammad Ghaazi Azzuhdi for revising the figures. Thanks also go to the anonymous reviewers for the helpful comments.

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