Publication: Discovery of antiviral molecules for dengue: in silico search and biological evaluation
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Date
2014
Authors
Cabarcas Montalvo, María
Maldonado Rojas, Wilson
Montes Grajales, Diana Lucía
Bertel Sevilla, Angela
Wagner Döbler, Irene
Sztajer, Helena
Reck, Michael
Flechas Alarcón, María Camila
Ocazionez, Raquel Elvira
Olivero Vebel, Jesús
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Abstract
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.