Molecular Modeling and Docking Studies of Neu5Ac2en analogues against Cholera toxin

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Molecular Modeling and Docking Studies of Neu5Ac2en analogues against Cholera toxin

Author Affiliations

¹Department of Bioinformatics, Karunya Univesity, Karunya Nagar, Coimabtore-641114, Tamil Nadu, INDIA

Res. J. Recent Sci., Volume 3, Issue (ISC-2013), Pages 408-414, (2014)

Abstract

Neu5Ac2en (2-deoxy-2, 3-didehydro-N-acetylneuraminic acid) analogues were modified in two different positions C-4 and C-9 were investigated using molecular modeling and molecular docking techniques. Cholera toxin is an protein complex made up of AB5 subunits secreted by the pathogenic organism Vibrio cholerae. In present days these organism shows resistance towards antibiotics. In our present study, Cholera toxin 3D protein structure was optimized and minimized using maestro v9.2. Twelve synthetic Neu5Ac2en analogues were modeled using ACD/ChemSketch and optimized in LigPrep which is a tool in Schrödinger suite. Active site of cholera toxin protein was analyzed using PDBsum database. Molecular docking of Neu5Ac2en analogues into the active site of cholera toxin protein were carried out using Glide v5.7. All the 12 analogues of Neu5Ac2en show good binding affinity towards the cholera toxin with least docking (XPG) energy score and also these analogues have good pharmacological properties. Neu5Ac2en analogues blocks the binding site residues of cholera toxin directly through intermolecular hydrogen bonding.

References

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Chen I.J. and Foloppe N.J., Drug-like bioactive structures and conformational coverage with the LigPrep/ ConfGen suite: comparison to programs MOE and catalyst, J Chem Inf Model., 50, 822-39 (2010)
Kaminski G.A., Friesner R.A., Tirado-Rives J. and Jorgensen W.L., Evaluation and reparametrization of the OPLS- AA force field for protein via comparison with accurate quantum chemical calculations on peptides, J Phys ChemB.,105, 6474-6477 (2001)
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Friesner R.A., Banks J.L., Murphy R.B., Halgren T.A., Klicic J.J. and Mainz D.T., et al., Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J Med Chem., 47, 1739 -1749 (2004)
Lengauer T. and Rarey M., Computational methods for biomolecular docking, Curr Opin Struct Biol., 402-406 (1996)
Friesner R.A., Murphy R.B., Repasky M.P., Frye L.L., Greenwood J.R. and Halgren T.A., et al., Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J Med Chem., 49, 6177-6196 (2006)
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[ref1] Schauer R., Achievements and challenges of sialic acid research, Glycoconj.J., 17, 485–499 (2000)

[ref2] Varki A.,Biological roles of oligosaccharides: all of the theories are correct, Glycobiology.,3, 97–130 (1993)

[ref3] Vimr E. R, Kalivoda K.A, Deszo E.L. and Steenbergen S.M., Diversity of microbial sialic acid metabolism, Microbiol. Mol. Biol., 68,132–153 (2004)

[ref4] Avril T., Wagner E.R., Willison H.J. and Crocker P.R., Sialic acid-binding immunoglobulin-like lectin 7 mediates selective recognition of sialylated glycans expressed on Campylobacter jejuni lipooligosaccharides, Infect. Immun., 74, 4133–4141 (2006)

[ref5] Vimr E., Steenbergen S. and Cieslewicz M., Biosynthesis of the polysialic acid capsule in Escherichia coli K1, J. Ind. Microbiol., 15, 352–360 (1995)

[ref6] Bauer S.H., Mansson M., Hood D.W., Richards J.C., Moxon E.R. and Schweda E.K.,A rapid and sensitive procedure for determination of 5--acetyl neuraminic acid in lipopolysaccharides of Haemophilus influenzae: a survey of 24 non-typeable H. influenzae strains, Carbohydr. Res., 335, 251–260 (2001)

[ref7] Schilling B., Goon S, Samuels N.M., Gaucher S.P., Leary J.A., Bertozzi C.R. and Gibson B.W., Biosynthesis of sialylated lipooligosaccharides in Haemophilus ducreyi is dependent on exogenous sialic acid and not mannosamine. Incorporation studies using -acylmannosamine analogues, -glycolylneuraminic acid, and 13C-labeled acetylneuraminic acid, Biochemistry., 40, 12666–12677 (2001), 408-414 (2014)

[ref8] Ram S., Sharma A.K., Simpson S.D., Gulati S., McQuillen D.P., Pangburn M.K. and Rice P.A., A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae, J. Exp. Med., 187, 743–752 (1998)

[ref9] Hammerschmidt S., Hilse R., van Putten J.P., Gerardy-Schahn R., Unkmeir A. and Frosch M., Modulation of cell surface sialic acid expression in Neisseria meningitidis via a transposable genetic element, EMBO J., 15, 192–198 (1998)

[ref10] Lewis A.L., Hensler M.E., Varki A. and Nizet V.,The group B streptococcal sialic acid O-acetyltransferase is encoded by neuD, a conserved component of bacterial sialic acid biosynthetic gene clusters, J. Biol. Chem., 281, 11186–11192 (2006)

[ref11] Varki N.M. and Varki A., Diversity in cell surface sialic acid presentations: implications for biology and disease, Lab Invest.,87, 851–857 (2007)

[ref12] Janas T. and Janas T., Polysialic acids: structure and properties. In Polysaccharides — Structural Diversity and Functional Versatility, Marcel Dekker., 707-727 (2005)

[ref13] Fgedi and Per., The organic chemistry of sugars., Washington, DC: Taylor and Francis,. 822–823 (2006)

[ref14] Meindl P., Bodo G., Palese P., Schulman J. and Tuppy H., Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-Nacetylneuraminic acid, Virology., 58, 457–63 (1974)

[ref15] Ryan K.J. and Ray C.G., Sherris Medical Microbiology., McGraw Hill. 375 (2004)ISBN 0-8385-8529-9.

[ref16] Holmgren J., Lo¨nnroth I. and Svennerholm L., Fixation and inactivation of cholera toxin by GM1 ganglioside, Scand J Infect Dis.,, 77–78 (1973)

[ref17] Kitaoko M, Miyata S.T., Unterweger D. and Pukatzki S., Antibiotic resistance mechanisms of Vibrio cholera, J Med Microbiol., 60, 397-407 (2011)

[ref18] Ethan A., Merritt, Sarfaty S., Focco VAN DEN Akker, Cecile L’HOIR, Joseph A., Martial and Wim G.J. Hol., Crystal structure of cholera toxin B-pentamer bound to receptor GM1 pentasaccharide, Protein Science., 3, 166-175 (1993)

[ref19] Sharmila, D.J.S. and veluraja R., Monosialogangliosides and Their Interaction with Cholera Toxin– Investigation by Molecular Modeling and Molecular Mechanics, Journal of Biomolecular Structure and Dynamics., 21, 591-613 (2004)

[ref20] Suzuki T., Ikeda K, Koyama N., Hosokawa C., Kogure T., Takahashi T., Jwa Hidari K.I-P, Miyamoto D., Tanaka K. and Suzuki Y., Inhibition of human parainfluenza virus type 1 sialidase by analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid, Glycoconjugate Journal., 18, 331-337 (2001)

[ref21] Chen I.J. and Foloppe N.J., Drug-like bioactive structures and conformational coverage with the LigPrep/ ConfGen suite: comparison to programs MOE and catalyst, J Chem Inf Model., 50, 822-39 (2010)

[ref22] Kaminski G.A., Friesner R.A., Tirado-Rives J. and Jorgensen W.L., Evaluation and reparametrization of the OPLS- AA force field for protein via comparison with accurate quantum chemical calculations on peptides, J Phys ChemB.,105, 6474-6477 (2001)

[ref23] Maestro 9.0, versuib 70110, Schrodinger, New York (2009)

[ref24] Friesner R.A., Banks J.L., Murphy R.B., Halgren T.A., Klicic J.J. and Mainz D.T., et al., Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J Med Chem., 47, 1739 -1749 (2004)

[ref25] Lengauer T. and Rarey M., Computational methods for biomolecular docking, Curr Opin Struct Biol., 402-406 (1996)

[ref26] Friesner R.A., Murphy R.B., Repasky M.P., Frye L.L., Greenwood J.R. and Halgren T.A., et al., Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J Med Chem., 49, 6177-6196 (2006)

[ref27] Merritt E.A., Sarfaty S., van den Akker F., L'Hoir C., Martial J.A. and Hol W.G., Crystal structure of cholera toxin B-pentamer bound to receptor GM1 pentasaccharide, Protein Sci., 3, 166-175 (1994)