2. Academic Validation
  3. Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies

Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies

  • Bioorg Med Chem. 2015 Feb 1;23(3):466-70. doi: 10.1016/j.bmc.2014.12.015.
Lorena Ramos Freitas de Sousa 1,  Hongmei Wu 2,  Liliane Nebo 3,  João Batista Fernandes 3,  Maria Fátima das Graças Fernandes da Silva 3,  Werner Kiefer 2,  Manuel Kanitz 4,  Jochen Bodem 5,  Wibke E Diederich 4,  Tanja Schirmeister 2,  Paulo Cezar Vieira 6
Affiliations

Affiliations

  • 1 Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil; Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
  • 2 Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
  • 3 Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil.
  • 4 Institut für Pharmazeutische Chemie,Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Hessen, Germany.
  • 5 Institut für Virologie und Immunbiologie, Julius-Maximillians-Universität Würzburg, Versbacher Str. 7, 97078 Würzburg, Germany.
  • 6 Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil. Electronic address: dpcv@ufscar.br.
PMID: 25564380 DOI: 10.1016/j.bmc.2014.12.015
Abstract

NS2B-NS3 is a serine protease of the Dengue virus considered a key target in the search for new Antiviral drugs. In this study Flavonoids were found to be inhibitors of NS2B-NS3 proteases of the Dengue virus serotypes 2 and 3 with IC50 values ranging from 15 to 44 μM. Agathisflavone (1) and myricetin (4) turned out to be noncompetitive inhibitors of Dengue virus serotype 2 NS2B-NS3 protease with Ki values of 11 and 4.7 μM, respectively. Docking studies propose a binding mode of the Flavonoids in a specific allosteric binding site of the Enzyme. Analysis of biomolecular interactions of quercetin (5) with NT647-NHS-labeled Dengue virus serotype 3 NS2B-NS3 protease by microscale thermophoresis experiments, yielded a dissociation constant KD of 20 μM. Our results help to understand the mechanism of inhibition of the Dengue virus serine protease by Flavonoids, which is essential for the development of improved inhibitors.

Keywords

Biflavone; Dengue virus; Flavonol; NS2B-NS3 protease.

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