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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

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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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