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-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 mu M. Three strong NS2B-NS3(pro) inhibitors were further confirmed as competitive inhibitors with Ki values of 4.0 +/- 0.4, 4.9 +/- 0.3, and 3.4 +/- 0.1 mu M, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3(pro) active site with inhibition compounds were also identified.