title: In vitro evaluation of novel inhibitors against the NS2B-NS3 protease of dengue fever virus type 4.
abstract: 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.
authors.forename: Thi Thanh Hanh
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Sun
authors.initials: S
authors.lastname: Lee
authors.forename: Hsi-Kai
authors.initials: HK
authors.lastname: Wang
authors.forename: Hsin-Yen
authors.initials: HY
authors.lastname: Chen
authors.forename: Ying-Ta
authors.initials: YT
authors.lastname: Wu
authors.forename: Simon C
authors.initials: SC
authors.lastname: Lin
authors.forename: Do-Won
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Biotechnology and Bioengineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Korea. best6238@gmail.com.
authors.forename: Doman
authors.initials: D
authors.lastname: Kim
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D003716:Dengue Virus / Q000145:classification / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D015870:Gene Expression; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011994:Recombinant Proteins; D012697:Serine Endopeptidases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases