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.
Highlights
Among members of the Flavivirus genus dengue virus (DENV) is responsible for the highest rate of disease and mortality and consists of a group of four serologically related viruses referred to as DENV types 1–4
A number of different strategies have been employed to search for DENV NS2B-NS3 protease inhibitors, including high-throughput screening [7,8,9], synthesizing rationally designed substrate-based peptidomimetics [10,11], cyclopeptide [12], and structure-based virtual screening (SBVS) [13,14,15] as well as screening natural products [16,17]
No enzyme activity was detected before induction or in the P. pastoris negative control without NS2B-NS3pro gene
Summary
Among members of the Flavivirus genus dengue virus (DENV) is responsible for the highest rate of disease and mortality and consists of a group of four serologically related viruses referred to as DENV types 1–4. Infection with these viruses results in a range of clinical diseases such as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome [1,2,3]. NS2B-NS3pro was expressed in Pichia pastoris culture This enzyme was used for in vitro enzyme inhibition assays against 36 compounds selected from VS of NS3pro using the GVSS. The novel compound inhibitors were tested for their IC50 values and used for an enzyme kinetic study
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