THE COMPUTATION OF CYCLIC PEPTIDE WITH PROLIN-PROLIN BOND AS FUSION INHIBITOR OF DENV ENVELOPE PROTEIN THROUGH MOLECULAR DOCKING AND MOLECULAR DYNAMICS SIMULATION

Published date: Sep 20 2015

Journal Title: KnE Life Sciences

Issue title: International Conference on Biological Sciences (ICBS-2013)

Pages: 416-421

DOI: 10.18502/kls.v2i1.185

Arli Aditya ParikesitDepartment of Chemistry, Faculty of Mathematics and Science, University of Indonesia

Hilyatuzzahroh .Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia

Andreas S NugrohoDepartment of Chemistry, Faculty of Mathematics and Science, University of Indonesia

Amalia HapsariDepartment of Chemistry, Faculty of Mathematics and Science, University of Indonesia

Usman Sumo Friend Tambunanusman@ui.ac.idDepartment of Chemistry, Faculty of Mathematics and Science, University of Indonesia

A disease that caused by dengue virus (DENV) has become the major health problem of the world. Nowadays, no effective treatment is available to overcome the disease due to the level of dengue virus pathogeneses. A novel treatment method such as antiviral drug is highly necessary for coping with the dengue disease. Envelope protein is one of the non-structural proteins of DENV, which engaged in the viral fusion process. It penetrates into the host cell to transfer its genetic material into the targeted cell followed by replication and establishment of new virus. Thus, the envelope protein can be utilized as the antiviral inhibitor target. The fusion process is mediated by the conformational change in the protein structure from dimer to trimer state. The previous research showed the existing cavity on the dimer structure of the envelope protein. The existing ligand could get into cavity of the envelope protein, stabilize the dimer structure or hamper the transition of dimer protein into trimer. In this fashion, the fusion process can be prevented. The aim of this research is designing the cyclic peptide with prolin-prolin bond as fusion inhibitor of DENV envelope protein through molecular docking and molecular dynamics simulation. The screening of 3,883 cyclic peptides, each of them connected by prolin-prolin bond, through molecular docking resulted in five best ligands. The result showed that PYRRP was the best ligand. PAWRP was also chosen as the best ligand because it showed good affinity with protein cavity. Stability of ligand-protein complex was analyzed by molecular dynamics simulation. The result showed that PYRRP ligand was able to support the stability of DENV envelope protein dimer structure at 310 K and 312 K. While PAWRP ligand actively formed complex with the DENV envelope protein at 310 K compared to 312 K. Thus the PYRRP ligand has a potential to be developed as DENV fusion inhibitor.

Keywords: dengue, envelope protein, fusion process, cavity, cyclic peptide, molecular docking, molecular dynamics

WHO. 2012. Dengue and Dengue Haemorrhagic Fever. World Health Organization.
Lindenbach, B.D., and C.M. Rice. 2007. Flaviridae: The Viruses and Their Replication.In Fundamental Virology. Knipe, D.M. & P.M. Howley (eds). pp. 991"1041. Lippincott.
Zuo, Z., et al. 2009. Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulation and Bioassays. Virology Journal,Vol.83(2):1060-1070.
Kampmann, T., et al. 2009. In silico Screening of Small Molecule Libraries using The Dengue Virus E Protein has Identified Compounds with Antiviral Activity Againts Multiple Flaviviruses.Antiviral Research, Vol.84:234"241.
Modis, Y., et al. 2003. Ligand-binding Pocket in the Dengue Virus Envelope Glycoprotein. Proc Natl Acad Sci USA, Vol.100(12): 6986-91.
Li, Z., et al. 2008. Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Protein. J MedChem, Vol.51(15):4660"4671.
Wang, Q.Y., et al. 2009. A Small-Molecule Dengue Virus Entry Inhibitor. Antimicrobial Agents and Chemotherapy, Vol.53(5):1823–1831.
Poh, M.K., et al. 2009. A Small Molecule Fusion Inhibitor of Dengue Virus. Antiviral Research, Vol.84:260"266.
Yennamali, R., et al. 2009. Identification of Novel Target Sites and an Inhibitor of The Dengue Virus E Protein. J. Computer Aided Mol,Vol.23:333–341.
Idrus, S., et al. 2012. Designing cyclopentapeptide inhibitor as potential antiviral drug for dengue virus NS5 methyltransferase. Bioinformation,Vol.8:348-352.
Tambunan, U.S.F. and Alamudi S. 2010. Designing cyclic peptide inhibitor of dengue virus NS3-NS2B protease by using molecular docking approach. Bioinformation,Vol.5(6): 250-254.
Tambunan, U.S.F., et al. 2011. Molecular Dynamics Simulation of DENV RNA-Dependent RNA-Polymerase with Potential Inhibitor of Disulfide Cyclic Peptide. Online Journal of Biological Sciences, Vol.11(2): 48-62.
Tambunan, U.S.F., et al. 2011. Computational Design of Disulfide Cyclic Peptide as Potential Inhibitor of Complex NS2B-NS3 Dengue Virus Protease. African Journal of Biotechnology, Vol.10(57): 12281"12290.
Pohl, S., R. Goddard, and S. Kubik. 2001. A New Cyclic Tetrapeptide Composed of Alternating L-Proline and 3-Aminobenzoic Acid Subunits. Tetrahedron Letters, Vol.42: 7555-7558.
Kitchen, D.B., et al. 2004. Docking and Scoring in Virtual Screening for Drug Discovery: Methods and Applications. Nature Reviews: Drug Discovery, Vol.3(11): 935–49.
Alonso, H., A.A. Bliznyuk, and J.E. Gready. 2006. Combining Docking and Molecular Dynamic Simulations in Drug Design. Medicinal Research Reviews, Vol.26(5):531-568.
Nurbaiti, S. 2009. The Role of Interface Domain Interactions on Thermal Stability of DNA Polymerase I ITB-1. International Journal of Integrative Biology. ISSN 0973-8363.