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

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

Chemistry & biodiversity

Manuel Augusto Llanos, Lucas Nicolás Alberca, Salomé Catalina Vilchez Larrea, Alejandra Cecilia Schoijet, Guillermo Daniel Alonso, Carolina Leticia Bellera, Luciana Gavernet, Alan Talevi

Affiliations

  1. National University of La Plata: Universidad Nacional de la Plata, Faculty of Exact Sciences, 47 & 115, La Plata, ARGENTINA.
  2. INGEBI: Instituto de Investigaciones en Ingenieria Genetica y Biologia Molecular, none, Vuelta de Obligado 2490, Buenos Aires, ARGENTINA.
  3. INGEBI: Instituto de Investigaciones en Ingenieria Genetica y Biologia Molecular, does not apply, Vuelta de Obligado 2490, Buenos Aires, ARGENTINA.
  4. National University of La Plata: Universidad Nacional de la Plata, Faculty of Exact Sciences, 47 & 115, 1900, La Plata, ARGENTINA.
  5. Universidad Nacional de La Plata, Biological Sciences, 47 & 115, B1900AKR, 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 TcrPDEb1 has not been solved so far, an homology model of the target was created using as template the structure of a TbrPDEb1. 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 compound 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-VCH GmbH.

Keywords: Molecular Docking, Molecular dynamics, Phosphodiesterase, Trypanosoma cruzi, Chagas disease

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