Molecular Modeling of T. rangeli, T. brucei gambiense, and T. evansi Sialidases in Complex with the DANA Inhibitor

Authors

  • Anderson H. Lima,

    1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil
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  • Paulo R. M. Souza,

    1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil
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  • Nelson Alencar,

    1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil
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  • Jerônimo Lameira,

    Corresponding author
    1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil
    2. Instituto de Ciências Biológicas, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil
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  • Thavendran Govender,

    1. School of Pharmacy and Pharmacology, University of KwaZulu Natal, Durban 4001, South Africa
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  • Hendrik G. Kruger,

    1. School of Chemistry, University of KwaZulu Natal, Durban 4001, South Africa
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  • Glenn E. M. Maguire,

    1. School of Chemistry, University of KwaZulu Natal, Durban 4001, South Africa
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  • Cláudio N. Alves

    1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil
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Corresponding author: Jerônimo Lameira, lameira@ufpa.br

Abstract

Trypanosomal (trans-) sialidases are enzymes that catalyze the transfer of sialic acid residues between host and parasite glycoconjugates. Herein, we have used homology modeling to construct the 3D structures of sialidases from Trypanosoma brucei and Trypanosoma evansi. Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations were used to determine the interaction energy between the 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid inhibitor and the three sialidases studied here. Our results suggest that the two constructed enzymes share the same basic fold motive of the Trypanosoma rangeli crystallographic structure. In addition, quantum mechanical/molecular mechanical molecular dynamics simulations show that the 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid inhibitor forms a stronger complex with Trypanosoma rangeli than with Trypanosoma brucei and Trypanosoma evansi sialidases. Finally, the interaction energy by residues shows that the arginine triad plays a decisive role to complex 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid with the enzyme through hydrogen bonding.

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