title: Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies.
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.
authors.affiliation: 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.
authors.forename: Lorena Ramos Freitas
authors.initials: LR
authors.lastname: de Sousa
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil.
authors.forename: Liliane
authors.initials: L
authors.lastname: Nebo
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil.
authors.forename: João Batista
authors.initials: JB
authors.lastname: Fernandes
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil.
authors.forename: Maria Fátima das Graças Fernandes
authors.initials: MF
authors.lastname: da Silva
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kiefer
authors.affiliation: Institut für Pharmazeutische Chemie,Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Hessen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kanitz
authors.affiliation: Institut für Virologie und Immunbiologie, Julius-Maximillians-Universität Würzburg, Versbacher Str. 7, 97078 Würzburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Bodem
authors.affiliation: Institut für Pharmazeutische Chemie,Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Hessen, Germany.
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, Washington Luís Km 235, 13565-905 São Carlos, São Paulo, Brazil. Electronic address: dpcv@ufscar.br.
authors.forename: Paulo Cezar
authors.initials: PC
authors.lastname: Vieira
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D005419:Flavonoids; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: Biflavone; Dengue virus; Flavonol; NS2B-NS3 protease