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Molecular modeling on pyruvate phosphate dikinase of Entamoeba histolytica and in silico virtual screening for novel inhibitors

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Abstract

Pyruvate phosphate dikinase (PPDK) is the key enzyme essential for the glycolytic pathway in most common and perilous parasite Entamoeba histolytica. Inhibiting the function of this enzyme could control the wide spread of intestinal infections caused by Entamoeba histolytica in humans. With this objective, we modeled the three dimensional structure of the PPDK protein. We used templates with 51% identity and 67% similarity to employ homology-modeling approach. Stereo chemical quality of protein structure was validated by protein structure validation program PROCHECK and VERIFY3D. Experimental proof available in literature along with the in silico studies indicated Lys21, Arg91, Asp323, Glu325 and Gln337 to be the probable active sites in the target protein. Virtual screening was carried out using the genetic docking algorithm GOLD and a consensus scoring function X-Score to substantiate the prediction. The small molecule libraries (ChemDivision database, Diversity dataset, Kinase inhibitor database) were used for screening process. Along with the high scoring results, the interaction studies provided promising ligands for future experimental screening to inhibit the function of PPDK in Entamoeba histolytica. Further, the phylogeny study was carried out to assess the possibility of using the proposed ligands as inhibitors in related pathogens.

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Abbreviations

ATP:

Adenosine triphosphate

AMP:

Adenosine monophosphate

PEP:

Phospho(enol)pyruvate

iP:

Inorganic phosphate

E-P:

Phosphorylhistidine intermediate

References

  1. Walsh JA (1986) Rev Infect Dis 8:228

    CAS  Google Scholar 

  2. Spinella S, Levavasseur E, Petek F, Rigothier MC (1999) Eur J Biochem 266:170

    Article  CAS  Google Scholar 

  3. http://www.who.int/entity/vaccine_research/documents/Parasitic_Diseases.pdf

  4. Petri WA Jr (2003) Trends Parasitol 19:523

    Article  CAS  Google Scholar 

  5. Samarawickrema NA, Brown DM, Upcroft JA, Thammapalerd N, Upcroft P (1997) J Antimicrob Chemother 40:833

    Article  CAS  Google Scholar 

  6. Que X, Brinen LS, Perkins P, Herdman S, Hirata K, Torian BE, Rubin H, McKerrow JH, Reed SL (2002) Mol Biochem Parasitol 119:23

    Article  CAS  Google Scholar 

  7. de Meester F, Shaw E, Scholze H, Stolarsky T, Mirelman D (1990) Infect Immun 58:1396

    Google Scholar 

  8. Byington CL, Dunbrack RL Jr, Whitby FG, Cohen FE, Agabian N (1997) Exp Parasitol 87:194

    Article  CAS  Google Scholar 

  9. Reeves RE (1984) Adv Parasitol 23:105

    Article  CAS  Google Scholar 

  10. McLaughlin J, Aley S (1985) J Protozool 32:221

    CAS  Google Scholar 

  11. Saavedra E, Encalada R, Pineda E, Jasso-Chavez R, Moreno-Sanchez R (2005) FEBS J 272:1767

    Article  CAS  Google Scholar 

  12. Saavedra-Lira E, Perez-Montfort R (1996) Arch Med Res 27:257

    CAS  Google Scholar 

  13. Cosenza LW, Bringaud F, Baltz T, Vellieux FM (2000) Acta Crystallogr D Biol Crystallogr 56:1688

    Article  CAS  Google Scholar 

  14. Wood HG, O’Brien EW, Micheales G (1977) Adv Enzymol Relat Areas Mol Biol 45:85

    Article  CAS  Google Scholar 

  15. Herzberg O, Chen CC, Kapadia G, McGuire M, Carroll LJ, Noh SJ, Dunaway-Mariano D (1996) Proc Natl Acad Sci USA 93:2652

    Article  CAS  Google Scholar 

  16. Ye D, Wei M, McGuire M, Huang K, Kapadia G, Herzberg O, Martin BM, Dunaway-Mariano D (2001) J Biol Chem 276:37630

    Article  CAS  Google Scholar 

  17. Thrall SH, Dunaway-Mariano D (1994) Biochemistry 33:1103

    Article  CAS  Google Scholar 

  18. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) J Mol Biol 215:403

    CAS  Google Scholar 

  19. Hubbard T, Andrews D, Caccamo M, Cameron G, Chen Y, Clamp M, Clarke L, Coates G, Cox T, Cunningham F, Curwen V, Cutts T, Down T, Durbin R, Fernandez-Suarez XM, Gilbert J, Hammond M, Herrero J, Hotz H, Howe K, Iyer V, Jekosch K, Kahari A, Kasprzyk A, Keefe D, Keenan S, Kokocinsci F, London D, Longden I, McVicker G, Melsopp C, Meidl P, Potter S, Proctor G, Rae M, Rios D, Schuster M, Searle S, Severin J, Slater G, Smedley D, Smith J, Spooner W, Stabenau A, Stalker J, Storey R, Trevanion S, Ureta-Vidal A, Vogel J, White S, Woodwark C, Birney E (2005) Nucleic Acids Res 33:D447

    Article  CAS  Google Scholar 

  20. Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD (2003) Nucleic Acids Res 31:3497

    Article  CAS  Google Scholar 

  21. Shindyalov IN, Bourne PE (1998) Protein Eng 11:739

    Article  CAS  Google Scholar 

  22. Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE, Burkhardt K, Feng Z, Gilliland GL, Iype L, Jain S, Fagan P, Marvin J, Padilla D, Ravichandran V, Schneider B, Thanki N, Weissig H, Westbrook JD, Zardecki C (2002) Acta Crystallogr D Biol Crystallogr 58:899

    Article  CAS  Google Scholar 

  23. Sali A, Blundell TL (1993) J Mol Biol 234:779

    Article  CAS  Google Scholar 

  24. Eswar N, John B, Mirkovic N, Fiser A, Ilyin VA, Pieper U, Stuart AC, Marti-Renom MA, Madhusudhan MS, Yerkovich B, Sali A (2003) Nucleic Acids Res 31:3375

    Article  CAS  Google Scholar 

  25. Wu CH, Yeh L-SL, Huang H, Arminski L, Castro-Alvear J, Chen Y, Hu Z, Kourtesis P, Ledley RS, Suzek BE, Vinayaka CR, Zhang J, Barker WC (2003) Nucleic Acids Res 31:345

    Article  CAS  Google Scholar 

  26. Karplus M, Petsko GA (1990) Nature 347:631

    Article  CAS  Google Scholar 

  27. Hagler AT, Huler E, Lifson S (1974) J Am Chem Soc 96:5319

    Article  CAS  Google Scholar 

  28. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) J Appl Crystallogr 26:283

    Article  CAS  Google Scholar 

  29. Ramachandran GN, Ramakrishnan C, Sasisekharan V (1963) J Mol Biol 7:95

    Article  CAS  Google Scholar 

  30. Eisenberg D, Luthy R, Bowie JU (1997) Methods Enzymol 277:396

    Article  CAS  Google Scholar 

  31. Huang B, Schroeder M (2006) BMC Struct Biol 6:19

    Article  CAS  Google Scholar 

  32. Lipinski CA, Lombardo F, Dominy B, Wand Feeney PJ (1997) Adv Drug Delivery Rev 23:3

    Article  CAS  Google Scholar 

  33. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) J Med Chem 45:2615

    Article  CAS  Google Scholar 

  34. CORINA Version 3.0, Molecular Networks GmbH, Erlangen, Germany (2004)

  35. Tetko I.V, Gasteiger J, Todeschini R, Mauri A, Livingstone D, Ertl P, Palyulin VA, Radchenko EV, Zefirov NS, Makarenko AS, Tanchuk VY, Prokopenko VV (2005) J Comput Aided Mol Des 19:453

    Article  CAS  Google Scholar 

  36. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727

    Article  CAS  Google Scholar 

  37. Wang R, Lai L, Wang S (2002) J Comput Aided Mol Des 16:11

    Article  CAS  Google Scholar 

  38. Csizmadia F (2000) J Chem Inf Comput Sci 40:323

    Article  CAS  Google Scholar 

  39. Buntrock RE (2002) J Chem Inf Comput Sci 42:1505

    Article  CAS  Google Scholar 

  40. Wallace AC, Laskowski RA, Thornton JM (1995) Protein Eng 8:127

    Article  CAS  Google Scholar 

  41. Ewing TJ, Makino S, Skillman AG, Kuntz ID (2001) J Comput Aided Mol Des 15:411

    Article  CAS  Google Scholar 

  42. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) Nucleic Acids Res 25:4876

    Article  CAS  Google Scholar 

  43. Kolaczkowski B, Thornton JW (2004) Nature 431:980

    Article  CAS  Google Scholar 

  44. Felsenstein J (1995) In: PHYLIP (Phylogeny Inference Package) Version 3.57c. Department of Genetics, University of Washington, Seattle, WA

  45. Ferrara P, Gohlke H, Price DJ, Klebe G, Brooks CL 3rd (2004) J Med Chem 47:3032

    Article  CAS  Google Scholar 

  46. Mohan V, Gibbs AC, Cummings MD, Jaeger EP, DesJarlais RL (2005) Curr Pharm Des 11:323

    Article  CAS  Google Scholar 

  47. Wang R, Lu Y, Wang S (2003) J Med Chem 46:2287

    Article  CAS  Google Scholar 

  48. Charifson PS, Corkery JJ, Murcko MA, Walters WP (1999) J Med Chem 42:5100

    Article  CAS  Google Scholar 

Download references

Acknowledgement

The authors thank Y. M. Ragothaman and the unknown reviewers for their thoughtful and constructive comments. The financial support to PS by NCAHG, SLS, JNU is acknowledged.

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Authors and Affiliations

  1. National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Preyesh Stephen, Audesh Bhat & R. N. K. Bamezai

  2. Center for Computational Biology and Bioinformatics, Jawaharlal Nehru University, Hall No. 4, Lecture Hall Complex, New Delhi, 110067, India

    Preyesh Stephen, Ramachandran Vijayan & N. Subbarao

Authors
  1. Preyesh Stephen
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  2. Ramachandran Vijayan
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  3. Audesh Bhat
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  4. N. Subbarao
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  5. R. N. K. Bamezai
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Corresponding author

Correspondence to R. N. K. Bamezai.

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Stephen, P., Vijayan, R., Bhat, A. et al. Molecular modeling on pyruvate phosphate dikinase of Entamoeba histolytica and in silico virtual screening for novel inhibitors. J Comput Aided Mol Des 22, 647–660 (2008). https://doi.org/10.1007/s10822-007-9130-2

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  • DOI: https://doi.org/10.1007/s10822-007-9130-2

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