6533b7cefe1ef96bd1257240

RESEARCH PRODUCT

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

Jochen BodemMaria Fátima Das Graças Fernandes Da SilvaManuel KanitzPaulo C. VieiraLiliane NeboWerner KieferWibke E. DiederichHongmei WuJoão B. FernandesLorena R.f. De SousaTanja Schirmeister

subject

Models MolecularProteasesSerine Proteinase Inhibitorsvirusesmedicine.medical_treatmentClinical BiochemistryPharmaceutical ScienceDengue virusmedicine.disease_causeAntiviral AgentsBiochemistryStructure-Activity Relationshipchemistry.chemical_compoundDrug DiscoverymedicineMolecular BiologyFlavonoidsSerine proteaseNS3ProteasebiologyMicroscale thermophoresisSerine EndopeptidasesOrganic ChemistryDengue VirusVirologyMolecular Docking SimulationKineticschemistryBiochemistryDocking (molecular)biology.proteinMolecular MedicineMyricetin

description

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.

yearjournalcountryeditionlanguage
2014-10-08Bioorganic & Medicinal Chemistry
https://doi.org/10.1016/j.bmc.2014.12.015