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Discovery of antiviral molecules for dengue: In silico search and biological evaluation.
Eur J Med Chem. 2016 Mar 03; 110:87-97.EJ

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 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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Cabarcas-Montalvo M
Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia.
Maldonado-Rojas W
Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia.
Montes-Grajales D
Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia.
Bertel-Sevilla A
Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia.
Wagner-Döbler I
Microbial Communication Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Sztajer H
Microbial Communication Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Reck M
Microbial Communication Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Flechas-Alarcon M
Laboratorio de Arbovirus, Centro de Investigaciones en Enfermedades Tropicales, Parque Tecnológico Guatiguará, Universidad Industrial de Santander, Piedecuesta, Colombia.
Ocazionez R
Laboratorio de Arbovirus, Centro de Investigaciones en Enfermedades Tropicales, Parque Tecnológico Guatiguará, Universidad Industrial de Santander, Piedecuesta, Colombia.
Olivero-Verbel J
Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia. Electronic address: joliverov@unicartagena.edu.co.

MeSH

Antiviral AgentsDengueDengue VirusDrug DiscoveryHep G2 CellsHumansMolecular Docking SimulationProtease InhibitorsSerine EndopeptidasesVirus Replication

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26807547

Citation

Cabarcas-Montalvo, Maria, et al. "Discovery of Antiviral Molecules for Dengue: in Silico Search and Biological Evaluation." European Journal of Medicinal Chemistry, vol. 110, 2016, pp. 87-97.
Cabarcas-Montalvo M, Maldonado-Rojas W, Montes-Grajales D, et al. Discovery of antiviral molecules for dengue: In silico search and biological evaluation. Eur J Med Chem. 2016;110:87-97.
Cabarcas-Montalvo, M., Maldonado-Rojas, W., Montes-Grajales, D., Bertel-Sevilla, A., Wagner-Döbler, I., Sztajer, H., Reck, M., Flechas-Alarcon, M., Ocazionez, R., & Olivero-Verbel, J. (2016). Discovery of antiviral molecules for dengue: In silico search and biological evaluation. European Journal of Medicinal Chemistry, 110, 87-97. https://doi.org/10.1016/j.ejmech.2015.12.030
Cabarcas-Montalvo M, et al. Discovery of Antiviral Molecules for Dengue: in Silico Search and Biological Evaluation. Eur J Med Chem. 2016 Mar 3;110:87-97. PubMed PMID: 26807547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of antiviral molecules for dengue: In silico search and biological evaluation. AU - Cabarcas-Montalvo,Maria, AU - Maldonado-Rojas,Wilson, AU - Montes-Grajales,Diana, AU - Bertel-Sevilla,Angela, AU - Wagner-Döbler,Irene, AU - Sztajer,Helena, AU - Reck,Michael, AU - Flechas-Alarcon,Maria, AU - Ocazionez,Raquel, AU - Olivero-Verbel,Jesus, Y1 - 2016/01/07/ PY - 2015/05/25/received PY - 2015/11/08/revised PY - 2015/12/14/accepted PY - 2016/1/26/entrez PY - 2016/1/26/pubmed PY - 2016/11/1/medline KW - Dengue protease inhibitor KW - Inhibitory activity KW - In vitro inhibition KW - Molecular docking KW - NS2B/NS3 complex SP - 87 EP - 97 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 110 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/26807547/Discovery_of_antiviral_molecules_for_dengue:_In_silico_search_and_biological_evaluation_ DB - PRIME DP - Unbound Medicine ER -