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Improving the Thrombin Inhibitory Activity of Glycyrrhizin, a Triterpenic Saponin, Through a Molecular Simplification of the Carbohydrate Moiety

Authors

  • Fernando T. de Paula,

    1. Laboratório de Diversidade Molecular e Química Medicinal (LaDMol-QM), Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
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  • Petrina Q. Frauches,

    1. Laboratório de Diversidade Molecular e Química Medicinal (LaDMol-QM), Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
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  • Conrado Pedebos,

    1. Grupo de Bioinformática Estrutural, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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  • Markus Berger,

    1. Laboratório de Bioquímica Farmacológica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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  • Simone C. B. Gnoatto,

    1. Laboratório de Fitoquímica, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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  • Grace Gossmann,

    1. Laboratório de Fitoquímica, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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  • Hugo Verli,

    1. Grupo de Bioinformática Estrutural, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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  • Jorge A. Guimarães,

    1. Laboratório de Bioquímica Farmacológica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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  • Cedric S. Graebin

    Corresponding author
    1. Laboratório de Diversidade Molecular e Química Medicinal (LaDMol-QM), Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
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Abstract

Glycyrrhizin, a saponin, and its aglycone glycyrrhetinic acid are natural products found in the Liquorice (Glycyrrhiza glabra L.) root extract. This saponin is known for its in vitro and in vivo thrombin inhibitory activity. The design and synthesis of five glycyrrhizin derivatives were carried out to improve the natural product activity. Compound 3b, a phthalic ester derivative of glycyrrhizin, presented a more pronounced thrombin inhibition (IC50 = 114.4 ± 1.3 μm) than the saponin (IC50 = 235.7 ± 1.4 μm). Molecular docking simulations performed to investigate the molecular interaction between compound 3b and the enzyme indicate that this product is, as previously determined for glycyrrhizin, an allosteric thrombin inhibitor.

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