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Computational studies on molecular interactions of 6-thioguanosine analogs with anthrax toxin receptor 1

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Abstract

Dormant endospores of Bacillus anthracis are the causative agent of anthrax, which is an acute disease for both human and animals. Anthrax has been practised as biological weapon because of two attributes: i) short duration of spore germination, and ii) lethal toxaemia of the vegetative stage. Pathogenesis is caused by the activity of edema toxin and lethal toxin. Protective antigen (PA), is an essential component of both complexes, binds to Anthrax Toxin Receptor (ATR) and mediates the lethality in mammals. The combination of vaccine and antibiotics are preferred to be effective treatment for destruction of the vegetative cell wall but could not be a successive destructor for endospores. So the present study is intended to identify the small molecules as a potential inhibitor for ATR1. 3D structure of Anthrax Toxin Receptor 1 (ATR1) was built by using the crystal structure of Anthrax Toxin Receptor 2 (ATR2) from Homo sapiens as template. Molecular docking of 6-thiogunaosine (6-TG) analogs was performed on the ATR1 model and effective inhibitor was selected based on the docking results. The docking results showed that the three residues in the ATR1 binding pocket (Phe162, Asp160, and Phe22) were essential for making hydrogen bond with the 2-(2-bromo-6-chloro-4H-purin-9(5H)-yl)- 5-(hydroxymethyl) tetrahydrofuran-3,4-diol (C11H13N3O5). The data presented here strongly indicate that the interactions of these four residues are necessary for a stronger binding of the ATR1 with C11H13N3O5. Also, the study proposed C11H13N3O5 as an effective inhibitor by the comparison of docking energy.

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References

  1. Abrami, L., Liu, S., Cosson, P., Leppla, S.H., Van der Goot, F.G. 2003. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrindependent process. J Cell Biol 160, 321–328.

    Article  PubMed  CAS  Google Scholar 

  2. Altschul, S.F., Gish, W., Miller, W., Myers, E.W., Lipman, D.J. 1990. Basic local alignment search tool. J Mol Biol 215, 403–410.

    PubMed  CAS  Google Scholar 

  3. Aparoy, P., Reddy, R.N., Guruprasad, L., Reddy, M.R., Reddana, P. 2008. Homology modelling of 5-lipooxygenase and hints for better inhibitor design. J Comput Aided Mol Des 22, 611–619.

    Article  PubMed  CAS  Google Scholar 

  4. Banks, D.J., Ward, S.C., Bradley, K.A. 2006. New insights into the functions of anthrax toxin. Expert Rev Mol Med 8, 1–18.

    Article  PubMed  Google Scholar 

  5. Bradley, K.A., Mogridge, J., Jonah, G., Rainey, A., Batty, S., Young, J.A. 2003. Binding of anthrax toxin to its receptor is similar to alpha integrin-ligand interactions. J Biol Chem 278, 49342–49347.

    Article  PubMed  CAS  Google Scholar 

  6. Brunger, A. 1992. X-PLOR, Version 3.1: A System for X-Ray Crystallography and NMR. Yale University, New Haven, CT.

    Google Scholar 

  7. Chenna, R., Sugawara, H., Koike, T., Lopez, R., Gibson, T.J., Higgins, D.G., Thompson, J.D. 2003. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 31, 3497–3500.

    Article  PubMed  CAS  Google Scholar 

  8. Diaz, A., Horjales, E., Rudino, P.E., Arrola, R., Hansberg, W. 2004. Unusual Cys-Tyr covalent bond in a large Cyp51A&B. J Mol Biol 342, 971–973.

    Article  PubMed  CAS  Google Scholar 

  9. Duesbery, N.S., Webb, C.P., Leppla, S.H., Gordon, V.M., Klimpel, K.R., Copeland, T.D., Ahn, N.G., Oskarsson, M.K., Fukasawa, K., Paull, K.D., Vande Woude, G.F. 1998. Proteolytic inactivation of MAPkinase by anthrax lethal factor. Sci 280, 734–737.

    Article  CAS  Google Scholar 

  10. Feller, S.E., MacKerell, A.D.Jr. 2000. An Improved empirical potential energy function for molecular simulations of phospholipids. J Phys Chem B 104, 7510–7515.

    Article  CAS  Google Scholar 

  11. Grubmuller, H., Heller, H., Windemuth, A., Schulten, K. 1991. Generalized Verlet algorithm for efficient molecular dynamics simulations with long-range interactions. Mol Simulat 6, 121–142.

    Article  Google Scholar 

  12. Guex, N., Peitsch, M.C. 1997. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 18, 2714–2723.

    Article  PubMed  CAS  Google Scholar 

  13. James, M.M., John, E.D., John, H.C., Stephen, F.M. 2011. Protien-ligand interactions: Thermodynamics effects associated with increasing nonpolar surface area. JACS 133, 18515–18521.

    Google Scholar 

  14. Kale, L.R., Skeel, M., Bhandarkar, R., Brunner, A., Gursoy, N., Krawetz, J., Phillips, A., Shinozaki, K., Varadarajan, K., Schulten, K. 1999. NAMD2: Greater scalability for parallel molecular dynamics. J Comput Phys 151, 283–286.

    Article  CAS  Google Scholar 

  15. Leppla, S.H. 1982. Anthrax toxin edema factor: A bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc Natl Acad Sci USA 79, 3162–3166.

    Article  PubMed  CAS  Google Scholar 

  16. Liu, H.H. 1999. Antibiotic resistance in bacteria: A current and future problem. Adv Exp Med Biol 455, 387–396.

    Article  PubMed  CAS  Google Scholar 

  17. Mackerell, A.D. Jr., Bashford, D., Bellott, M., Dunbrack, R.L. Jr., Evanseck, J.D., Field, M.J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph-McCarthy, D., Kuchnir, L., Kuczera, K., Lau, F.T.K., Mattos, C., Michnick, S., Ngo, T., Nguyen, D.T., Prodhom, B., Reiher, W.E., Roux, B., Schlenkrich, M., Smith, J.C., Stote, R., Straub, J.E., Watanabe, M., Wiokiewicz-Kuczera, J., Yin, D., Karplus, M. 1998. All hydrogen empricial potential for molecular modeling and dynamic was studies of protein using the CHARMM22 force field. J Phys Chem 281, 1630–1635.

    Google Scholar 

  18. MacKerell, A.D. Jr., Banavali, N., Foloppe, N. 2001. Development and current status of the CHARMM force field for nucleic acids. Biopolymers 56, 257–265.

    Article  Google Scholar 

  19. Monique, A., Raynal, C.S., Adel, M.N., Ludmyl, A., Jurgen, B., Ernesto, A.S. 2007. Identification of an in vivo inhibitor of Bacillus anthracis spore germination. J Biol Chem 282, 12112–12118.

    Google Scholar 

  20. Purohit, R., Sethumadhavan, R. 2009. Structural basis for the resilience of darunavir (TMC114) resistance major flap mutation of HIV-1 protease. Interdiscip Sci Comput Life Sci 1, 320–328.

    Article  CAS  Google Scholar 

  21. Ramamoorthy, M., Chinnaiah, S.V., Maruthamuthu, R., Ekambaram, R. 2008. A study of molecular modeling, dynamics and mechanics of cyp2b6 and nk binding using Hex. JCIB 1, 109–114.

    Google Scholar 

  22. Sali, A., Blundell, T.L. 1993. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234, 779–815.

    Article  PubMed  CAS  Google Scholar 

  23. Thompson, J.D., Higgins, D.G., Gibson, T.J. 1994. CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22, 4673–4680.

    Article  PubMed  CAS  Google Scholar 

  24. Van der Goot, F.G., Young, J.A. 2009. Receptors of anthrax toxin and cell entry. Mol Aspects Med 6, 406–412.

    Article  Google Scholar 

  25. Vitale, G., Pelizzari, R., Recchi, C., Napolitani, G., Mock, M., Montecucco, C. 1998. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun 248, 706–711.

    Article  PubMed  CAS  Google Scholar 

  26. Young, J.A., Collier, R. 2007. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem 76, 243–265.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, 620024, India

    Nitin K. Singh, Britto C. Pakkkianathan, Mani Kannan & Muthukalingan Krishnan

  2. Advanced Instrumentation Research Facility, Jawaharlal Nehru University, New Delhi, 110067, India

    Manish Kumar

  3. Department of Bioinformatics, Global Insitute of Biotechnology, Himayat Nagara, Hyderabad, 500029, India

    Jayssima R. Daddam

  4. UGC-Networking Resource Centre, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, India

    Sridhar Jayavel

  5. Florida Center for Heterocyclic Compounds, University of Florida, Gainesville, Florida, 32611, USA

    Girinath G. Pillai

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  1. Nitin K. Singh
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  2. Britto C. Pakkkianathan
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  8. Muthukalingan Krishnan
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Correspondence to Muthukalingan Krishnan.

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The authors contributed to the paper equally.

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Singh, N.K., Pakkkianathan, B.C., Kumar, M. et al. Computational studies on molecular interactions of 6-thioguanosine analogs with anthrax toxin receptor 1. Interdiscip Sci Comput Life Sci 4, 183–189 (2012). https://doi.org/10.1007/s12539-012-0126-9

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  • DOI: https://doi.org/10.1007/s12539-012-0126-9

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