Receptor-Dependent 4D-QSAR Analysis of Peptidemimetic Inhibitors of Trypanosoma cruzi Trypanothione Reductase with Receptor-Based Alignment

Authors

  • Samuel Silva da Rocha Pita,

    Corresponding author
    1. Universidade Federal do Rio de Janeiro, PPGQu, IQ, CT, LabMMol, 21949-900, Rio de Janeiro, RJ, Brazil
      Corresponding author: MGA, magaly@iq.ufrj.br; SSRP, samuel.pita@ufba.br
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    • Permanent address: Universidade Federal da Bahia, Faculdade de Farmácia, LABIMM, 40170-115, Salvador, BA, Brazil

  • Magaly Girão Albuquerque,

    Corresponding author
    1. Universidade Federal do Rio de Janeiro, PPGQu, IQ, CT, LabMMol, 21949-900, Rio de Janeiro, RJ, Brazil
      Corresponding author: MGA, magaly@iq.ufrj.br; SSRP, samuel.pita@ufba.br
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  • Carlos Rangel Rodrigues,

    1. Universidade Federal do Rio de Janeiro, CCS, Faculdade de Farmácia, ModMolQSAR, 21941-590, Rio de Janeiro, RJ, Brazil
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  • Helena Carla Castro,

    1. Universidade Federal Fluminense, CEG, Instituto de Biologia, LaBioMol, 24210-130, Niteroi, RJ, Brazil
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  • Anton J. Hopfinger

    1. University of New Mexico, College of Pharmacy, 87131-0001, Albuquerque, New Mexico, USA
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Corresponding author: MGA, magaly@iq.ufrj.br; SSRP, samuel.pita@ufba.br

Abstract

Receptor-dependent four-dimensional quantitative structure–activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q2 above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand–enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases not yet studied.

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