Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Eur J Med Chem. 2016 Mar 3;110:87-97. doi: 10.1016/j.ejmech.2015.12.030. Epub 2016 Jan 7.


Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation.

Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that are capable of inhibiting the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrate and the complex NS2B/NS3 obtained by recombinant DNA techniques. HepG2 cells infected with dengue virus serotype 2 were used to test the activity against dengue virus replication.

Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that were capable of inhibiting this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested.

Conclusions: Chemicals CID 54681617, CID 54692801 and CID 54715399 were strong inhibitors of NS2B/NS3, with IC50 values (μM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9%, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors.

General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.

Keywords: Dengue protease inhibitor; Inhibitory activity; In vitro inhibition; Molecular docking; NS2B/NS3 complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Dengue / drug therapy*
  • Dengue / virology
  • Dengue Virus / drug effects*
  • Dengue Virus / enzymology
  • Drug Discovery
  • Hep G2 Cells
  • Humans
  • Molecular Docking Simulation
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Serine Endopeptidases / metabolism
  • Virus Replication / drug effects


  • Antiviral Agents
  • Protease Inhibitors
  • NS3 protease, dengue virus
  • Serine Endopeptidases