In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4

Molecules

Thi Thanh Hanh Nguyen¹  Sun Lee¹  Hsi-Kai Wang²  Hsin-Yen Chen²  Ying-Ta Wu³  Simon C. Lin²  Do-Won Kim⁴ 

[1]Department of Biotechnology and Bioengineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Korea

[2] E-Mails:

[3]Research Center for Information Technology Innovation, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, Taiwan

[4] E-Mails:

[5]Genomics Research Center, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, Taiwan

[6] E-Mail:

[7]Department of Physics, Gangneung-Wonju National University, Gangneung 210-702, Korea

[8] E-Mail:

关键词: dengue fever;    inhibitors;    NS2B-NS3 protease;    virtual screening;   

DOI  :  10.3390/molecules181215600

来源: mdpi

【 摘 要 】

The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3^pro) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3^pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3^pro expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC₅₀ values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3^pro inhibitors were further confirmed as competitive inhibitors with K_i values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3^pro active site with inhibition compounds were also identified.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.