SCREENING OF COMPETITIVE INHIBITOR OF HEPARAN SULFATE IN JAPANESE ENCEPHALITIS
Objective: Japanese encephalitis virus (JEV) causes central nervous system inflammatory disease Japanese encephalitis (JE), which is mainly caused
in children below 15 years of age. On an estimate, there are around 3 billion people at the risk and the disease is continuously spreading globally. The
JEV belongs to Flavivirdiae family and has RNA genome. JEV envelope protein domain III (D-III) binds to the Heparan sulfate present on the cell surface
and initiates the infection which causes the disease in children.
Methods: The drug discovery and development process has become more quantitative and much more computational in recent years. In this study,
comparative molecular docking studies of 200 zinc database compounds and Heparan sulfate were done with D-III of JEV using Autodock 4.2 and the
results were analyzed on the basis of binding energy, inhibition constant, and number of hydrogen bonds. The results were also analyzed by studying
the absorption, distribution, metabolism, and excretion (ADME-T) properties of the compounds using admetSAR server.
Results: Best three lead molecules zinc_8964844 zinc_8964845, zinc_12660861 were chosen based on the binding energy, inhibition constant and
ADME properties among a set of 200 ligands that can act as the competitive inhibitor of the Heparan sulfate, which presents on the surface of the host
cell and mediates the attachment and binding of the virus to the host cell.
Conclusion: These compounds can act as the competitive inhibitor of the Heparan sulfate and they can be validated further as a drug for the treatment of JE.
Keywords: Japanese encephalitis, Domain-III, Heparan sulfate, Autodock, Autodock, Absorption, Distribution, Metabolism, Excretion.
1. Dundas J, Ouyang Z, Tseng J, Binkowski A, Turpaz Y, Liang J. CAST p: Computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic Acids Res 2006;34:W116-8.
2. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, et al. Admet SAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 2012;52(11):3099-105.
3. Goodsell DS, Morris GM, Halliday RS, Huey R, Belew RK, Olson AJ. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 1998;19(14):1639-62.
4. 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. New Model Anal Health Inform Bioinform 2013;2:231-43.
5. Karabatsos N. International Catalogue of Arboviruses. San Antonio, Texas: The American Society of Tropical Medicine and Hygiene; 1985.
6. Chambers TJ, Hahn CS, Galler R, Rice CM. Flavivirus genome organization, expression, and replication. Annu Rev Microbiol 1990;44:649-88.
7. Kaczor A, Matosiuk D. Structure based virtual screening for novel inhibitor of Japanese encephalitis virus NS3 helicase/nucleoside triphosphate. FMES Immunol Med Microbiol 2010;58(1):91-101.
8. Lin CW, Wu SC. A functional epitope determinant on domain III of the Japanese encephalitis virus envelope protein interacted with neutralizing-antibody combining sites. J Virol 2003;77(4):2600-6.
9. Luca VC, AbiMansour J, Nelson CA, Fremont DH. Crystal structure of the Japanese encephalitis virus envelope protein. J Virol 2012;86(4):2337-46.
10. Mukherjee G, Jayaram B. A rapid identification of hit molecules for target proteins via physico-chemical descriptors. Phys Chem Chem Phys 2013;15(23):9107-16.
11. Oâ€™Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: An open chemical toolbox. J Cheminform 2011;3:33.
12. Sayeed U, Wadhwa G, Khan MK, Jamal QM, Akhtar S, Khan MS. An immuno-informatics driven epitope study from the molecular interaction of JEV non-structural (NS) proteins with ribophorin (RPN). Bioinformation 2014;10(8):496-501.
13. Tiwari S, Singh RK, Tiwari R, Dhole TN. Japanese encephalitis: A review of the Indian perspective. Braz J Infect Dis 2012;16(6):564-73.
14. Unni SK, RuÅ¾ek D, Chhatbar C, Mishra R, Johri MK, Singh SK. Japanese encephalitis virus: From genome to infectome. Microbes Infect 2011;13(4):312-21.
15. Wallace AC, Laskowski RA, Thornton JM. Ligplot: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995;8(2):127-34.
16. Wu KP, Wu CW, Tsao YP, Kuo TW, Lou YC, Lin CW, et al. Structural basis of a flavivirus recognized by its neutralizing antibody: Solution structure of the domain III of the Japanese encephalitis virus envelope protein. J Biol Chem 2003;278(46):46007-13.
17. Zidane N, Dussart P, Bremand L, Villani ME, Bedouelle H. Thermodynamic stability of domain III from the envelope protein of flaviviruses and its improvement by molecular design. Protein Eng Des Sel 2013;26(6):389-99.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.