IDENTIFICATION OF INHIBITORS OF DENGUE VIRUS (DENV1, DENV2 AND DENV3) NS2B/ NS3 SERINE PROTEASE: A MOLICULAR DOCKING AND SIMULATION APPROACH
Dengue is one of the fatal diseases, which are becoming a global health burden from few decades. Dengue fever, dengue hemorrhagic fever and
dengue shock syndrome, caused by dengue virus (DENV), which completes its life cycle in mosquito i.e. Aedes aegyti, and human (DENV), and infect
about various individuals every year. The objective of this study is to find a potent inhibitor of DENV (DENV1, DENV2 and DENV3). In the present
study, NS2b/NS3 serine protease complex in targeted for the screening of the suitable inhibitors for DENV (DENV1, DENV2 and DENV 3). Therefore,
the NS2b/NS3 serine protease complex structures were retrieved from the RCSB Protein Databank. The unliganded protein structures were docked,
and best three selected and analyzed. A molecular dynamic simulation is also performed to investigate the conformational and positional changes
of ligand that provide insights into the binding stability. It was observed that three of screened compounds have the maximum potential against the
protein. The analysis was performed on the basis of scoring and binding ability and one of them indicated minimum energy score with high number
of interactions with active site residues and the simulation study revealed that this selected ligand could efficiently bind to the NS2b/NS3 protease.
These findings conclude that this selected ligand could be a promising inhibitor of all three serotypes of DENV as drug targets.
Keywords: Dengue virus, Aedes aegyti, Flaviviridae, Serine protease, Docking.
2. Mackenzie JS, Gubler DJ, Petersen LR. Emerging flaviviruses: The spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 2004;10:S98-109.
3. Kee LY, Tan SK, Wahab HA, Yusuf R, Rahman NA. Non substrate based inhibitor of dengue virus serine protease: A molecular docking approach to study binding interaction between protease and inhibitors. Asia Pac J Mol Biol Biotechnol 2007;15:53-9.
4. Frimayanti N, Chee CF, Zain SM, Rahman NA. Design of new competitive dengue NS2B/NS3 protease inhibitors - A computational approach. Int J Mol Sci 2011;12:1089-100.
5. Ilyas M, Rahman Z, Shamas S, Alam M, Israr M, Masood K. Bioinformatic analysis of envelope glycoprotein E epitomes of dengue virus type 3. Afr J biotechnol 2010;10:3528-33.
6. Tambunan US, Parikshit AA, Taufik HR, Syamsudin FA. In silico analysis of envelop dengue virus-2 and envelop dengue virus-3 protein as the backbone of dengue virus tetravalent vaccine by using homology modeling method. Online J Biol Sci 2009;9:6-16.
7. Bianchi E, Pessi A. Inhibiting viral proteases: Challenges and opportunities. Biopolymers 2002;66(2):101-14.
8. Chambers TJ, Nestorowicz A, Amberg SM, Rice CM. Mutagenesis of the yellow fever virus NS2B protein: Effects on proteolytic processing, NS2B-NS3 complex formation, and viral replication. J Virol 1993;67(11):6797-807.
9. Leyssen P, de Clercq E, Neyts J. Perspective for the treatment of infections with flaviviridae. Clin Microbiol 2003;13:67-82.
10. Sampath A, Padmanabhan R. Molecular targets for flavivirus drug discovery. Antiviral Res 2009;81(1):6-15.
11. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, et al. Clustal W and Clustal X version 2.0. Bioinformatics 2007;23(21):2947-8.
12. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The Protein Data Bank. Nucleic Acids Res 2000;28(1):
13. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera â€“ A visualization system for exploratory research and analysis. J Comput Chem 2004;25(13):1605-12.
14. Dundas J, Ouyang Z, Tseng J, Binkowski A, Turpaz Y, Liang J. CASTp: Computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic Acids Res 2006;34(Web Server issue):W116-8.
15. Irwin JJ, Shoichet BK. ZINC â€“ A free database of commercially available compounds for virtual screening. J Chem Inf Model 2005;45(1):177-82.
16. Oâ€™Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform 2011;3:33.
17. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009;30(16):2785-91.
18. Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995;8:127-34.
19. Kumar PS, Gopi G, Anitha K. Molicular docking study on dipeptidyl peptidase 4 inhibitor. Int J Res Dev Pharm Life Sci 2013;2(5):602â€‘10.
20. Berendsen HJ, Spoel DV, Drunen RV. GROMACS: A message-passing parallel molecular dynamics implementation. Comput Phys Commun 1995;91:43-56.
21. Lindahl E, Hess B, Spoel DV. GROMACS 3.0: A package for molecular simulation and trajectory analysis. J Mol Model 2001;7:306-17.
22. SchÃ¼ttelkopf AW, van Aalten DM. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 2004;60(Pt 8):1355-63.
23. Gupta SK, Singh S, Nischal A, Pant KK, Seth PK. Molecular docking and simulation studies towards exploring antiviral compounds against envelope protein of Japanese encephalitis virus. Netw Model Anal Health Inform Bioinform 2013;2:231-43.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.