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Llanos MA, Alberca LN, Larrea SCV, et al. Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1. Chem Biodivers. 2021;e2100712doi: 10.1002/cbdv.202100712.
Llanos, M. A., Alberca, L. N., Larrea, S. C. V., Schoijet, A. C., Alonso, G. D., Bellera, C. L., Gavenet, L., & Talevi, A. (2021). Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1. Chemistry & biodiversity, e2100712. https://doi.org/10.1002/cbdv.202100712
Llanos, Manuel A, et al. "Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1." Chemistry & biodiversity vol. (2021): e2100712. doi: https://doi.org/10.1002/cbdv.202100712
Llanos MA, Alberca LN, Larrea SCV, Schoijet AC, Alonso GD, Bellera CL, Gavenet L, Talevi A. Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1. Chem Biodivers. 2021 Nov 23;e2100712. doi: 10.1002/cbdv.202100712. Epub 2021 Nov 23. PMID: 34813143.
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Chem Biodivers. 2021 Nov 23;e2100712. doi: 10.1002/cbdv.202100712. Epub 2021 Nov 23.

Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1.

Chemistry & biodiversity

Manuel A Llanos, Lucas N Alberca, Salomé C Vilchez Larrea, Alejandra C Schoijet, Guillermo D Alonso, Carolina L Bellera, Luciana Gavenet, Alan Talevi

Affiliations

  1. Laboratory of Bioactive Research and Development (LIDeB), Faculty of Exact Sciences, University of La Plata - 47 and 115, La Plata, Buenos Aires, Argentina.
  2. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Buenos Aires, Argentina.
  3. National Scientific and Technical Research Council (CONICET) - CCT, La Plata, Argentina.

PMID: 34813143 DOI: 10.1002/cbdv.202100712

Abstract

Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new therapeutic agents. Because the experimental structure of Trypanosoma cruzi PDEb1 (TcrPDEb1) has not been solved so far, an homology model of the target was created using the structure of Trypanosoma brucei PDEb1 (TbrPDEb1) as a template. The model was refined by extensive enhanced sampling molecular dynamics simulations, and representative snapshots were extracted from the trajectory by combined clustering analysis. This structural ensemble was used to develop a structure-based docking model of the target. The docking accuracy of the model was validated by redocking and cross-docking experiments using all available crystal structures of TbrPDEb1, whereas the scoring accuracy was validated through a retrospective screen, using a carefully curated dataset of compounds assayed against TbrPDEb1 and/or TcrPDEb1. Considering the results from in silico validations, the model may be applied in prospective virtual screening campaigns to identify novel hits, as well as to guide the rational design of potent and selective inhibitors targeting this enzyme.

© 2021 Wiley-VHCA AG, Zurich, Switzerland.

Keywords: Chagas disease; Trypanosoma cruzi; homology modeling; molecular docking; molecular dynamics; phosphodiesterase

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