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Molecular dynamics studies of a hexameric purine nucleoside phosphorylase

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Abstract

Purine nucleoside phosphorylase (PNP) (EC.2.4.2.1) is an enzyme that catalyzes the cleavage of N-ribosidic bonds of the purine ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme is involved in purine-salvage pathway and has been proposed as a promising target for design and development of antimalarial and antibacterial drugs. Recent elucidation of the three-dimensional structure of PNP by X-ray protein crystallography left open the possibility of structure-based virtual screening initiatives in combination with molecular dynamics simulations focused on identification of potential new antimalarial drugs. Most of the previously published molecular dynamics simulations of PNP were carried out on human PNP, a trimeric PNP. The present article describes for the first time molecular dynamics simulations of hexameric PNP from Plasmodium falciparum (PfPNP). Two systems were simulated in the present work, PfPNP in ligand free form, and in complex with immucillin and sulfate. Based on the dynamical behavior of both systems the main results related to structural stability and protein-drug interactions are discussed.

Purine nucleoside phosphorylase is a potential target for the development of antibacterial and antimalarial drugs. Molecular dynamics simulations have been performed to evaluate the structural and dynamical properties of PfPNP. Two systems were simulated, the protein in the apo form and a second system for the ternary complex involving PfPNP, SO4, and an inhibitor.

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Acknowledgments

This work was supported by grants from CNPq (Conselho Nacional de Pesquisas, Brazil), CAPES and Instituto do Milênio (CNPq-MCT). RAC would like to thank CNPq for the fellowship. WFA and RGS are senior researchers of CNPq

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Authors and Affiliations

  1. Programa de Pós Graduação em Biologia Experimental – PGBIOEXP, Universidade Federal de Rondônia, Porto Velho, RO, Brazil

    Fernando Berton Zanchi & Rodrigo Guerino Stabeli

  2. IPEPATRO – Instituto de Pesquisa em Patologias Tropicais/Fundação Oswaldo Cruz - Fiocruz Noroeste, Porto Velho, RO, Brazil

    Fernando Berton Zanchi & Rodrigo Guerino Stabeli

  3. Programa de Pós Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Rafael Andrade Caceres & Walter Filgueira de Azevedo Jr.

  4. Faculdade de Biociências, Laboratório de Bioquímica Estrutural, Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Rafael Andrade Caceres & Walter Filgueira de Azevedo Jr.

Authors
  1. Fernando Berton Zanchi
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  2. Rafael Andrade Caceres
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  3. Rodrigo Guerino Stabeli
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  4. Walter Filgueira de Azevedo Jr.
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Corresponding author

Correspondence to Walter Filgueira de Azevedo Jr..

Additional information

F. B. Z and R. A. C. contributed equally to this work, the order of authorship being arbitrary.

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Zanchi, F.B., Caceres, R.A., Stabeli, R.G. et al. Molecular dynamics studies of a hexameric purine nucleoside phosphorylase. J Mol Model 16, 543–550 (2010). https://doi.org/10.1007/s00894-009-0557-3

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  • DOI: https://doi.org/10.1007/s00894-009-0557-3

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