In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro) 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 screeni...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2013-12-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1420-3049/18/12/15600 |
| _version_ | 1811273889458683904 |
|---|---|
| author | Thi Thanh Hanh Nguyen Sun Lee Hsi-Kai Wang Hsin-Yen Chen Ying-Ta Wu Simon C. Lin Do-Won Kim Doman Kim |
| author_facet | Thi Thanh Hanh Nguyen Sun Lee Hsi-Kai Wang Hsin-Yen Chen Ying-Ta Wu Simon C. Lin Do-Won Kim Doman Kim |
| author_sort | Thi Thanh Hanh Nguyen |
| collection | DOAJ |
| description | The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro) 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-NS3pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3pro 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-NS3pro inhibitors were further confirmed as competitive inhibitors with Ki 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 NS3pro active site with inhibition compounds were also identified. |
| first_indexed | 2024-04-12T23:07:44Z |
| format | Article |
| id | doaj.art-072b0e1870434811ab16698b37b0d3d7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T23:07:44Z |
| publishDate | 2013-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-072b0e1870434811ab16698b37b0d3d72022-12-22T03:12:52ZengMDPI AGMolecules1420-30492013-12-011812156001561210.3390/molecules181215600molecules181215600In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4Thi Thanh Hanh Nguyen0Sun Lee1Hsi-Kai Wang2Hsin-Yen Chen3Ying-Ta Wu4Simon C. Lin5Do-Won Kim6Doman Kim7Department of Biotechnology and Bioengineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, KoreaDepartment of Biotechnology and Bioengineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, KoreaResearch Center for Information Technology Innovation, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, TaiwanResearch Center for Information Technology Innovation, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, TaiwanResearch Center for Information Technology Innovation, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, TaiwanDepartment of Physics, Gangneung-Wonju National University, Gangneung 210-702, KoreaDepartment of Biotechnology and Bioengineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, KoreaThe discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro) 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-NS3pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3pro 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-NS3pro inhibitors were further confirmed as competitive inhibitors with Ki 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 NS3pro active site with inhibition compounds were also identified.http://www.mdpi.com/1420-3049/18/12/15600dengue feverinhibitorsNS2B-NS3 proteasevirtual screening |
| spellingShingle | Thi Thanh Hanh Nguyen Sun Lee Hsi-Kai Wang Hsin-Yen Chen Ying-Ta Wu Simon C. Lin Do-Won Kim Doman Kim In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 Molecules dengue fever inhibitors NS2B-NS3 protease virtual screening |
| title | In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 |
| title_full | In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 |
| title_fullStr | In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 |
| title_full_unstemmed | In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 |
| title_short | In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 |
| title_sort | in vitro evaluation of novel inhibitors against the ns2b ns3 protease of dengue fever virus type 4 |
| topic | dengue fever inhibitors NS2B-NS3 protease virtual screening |
| url | http://www.mdpi.com/1420-3049/18/12/15600 |
| work_keys_str_mv | AT thithanhhanhnguyen invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT sunlee invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT hsikaiwang invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT hsinyenchen invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT yingtawu invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT simonclin invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT dowonkim invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 AT domankim invitroevaluationofnovelinhibitorsagainstthens2bns3proteaseofdenguefevervirustype4 |