Discovery of antiviral molecules for dengue: in silico search and biological evaluation
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 can inhibit the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrateand the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. 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 could inhibit 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 CID54681617, CID54692801 and CID54715399 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.
| Main Authors: | , , , , , , , , , |
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| Format: | Otros biblioteca |
| Language: | eng |
| Published: |
2014
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| Subjects: | Dengue, Vectores, > Insectos, Vectores patógenos, Plantas medicinales, Dengue protease inhibitor, NS2B/NS3 complex, Molecular docking, In vitro inhibition, Inhibitory activity, Aceites esenciales, Bioquímica vegetal, Biología molecular, Tecnología química, Catalizadores, |
| Online Access: | http://repositorio.colciencias.gov.co/handle/11146/34204 |
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