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

被引：113

作者：

Freitas de Sousa, Lorena Ramos ^{[1
,2
]}

Wu, Hongmei ^{[2
]}

Nebo, Liliane ^{[1
]}

Fernandes, Joao Batista ^{[1
]}

das Gracas Fernandes da Silva, Maria Fatima ^{[1
]}

Kiefer, Werner ^{[2
]}

Kanitz, Manuel ^{[3
]}

Bodem, Jochen ^{[4
]}

Diederich, Wibke E. ^{[3
]}

Schirmeister, Tanja ^{[2
]}

Vieira, Paulo Cezar ^{[1
]}

机构：

[1] Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Paulo, Brazil

[2] Johannes Gutenberg Univ Mainz, Inst Pharm & Biochem, D-55128 Mainz, Germany

[3] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Hessen, Germany

[4] Univ Wurzburg, Inst Virol & Immunbiol, D-97078 Wurzburg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 03期

关键词：

Biflavone; Flavonol; Dengue virus; NS2B-NS3; protease; ANTIVIRAL ACTIVITY; TYPE-2; PROTEASE; NS3; PROTEIN; DERIVATIVES; HELICASE; DOMAIN;

D O I：

10.1016/j.bmc.2014.12.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M. Agathisflavone (1) and myricetin (4) turned out to be noncompetitive inhibitors of dengue virus serotype 2 NS2B-NS3 protease with K-i values of 11 and 4.7 mu M, 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 K-D of 20 mu M. 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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：466 / 470

页数：5

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