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Artículo

Discovery of novel dengue virus entry inhibitors via a structure-based approach

Leal, Emilse SoledadIcon ; Aucar, María GabrielaIcon ; Gebhard, Leopoldo GermanIcon ; Iglesias, Nestor GabrielIcon ; Pascual, María José; Casal, Juan JoséIcon ; Gamarnik, Andrea VanesaIcon ; Cavasotto, Claudio NorbertoIcon ; Bollini, MarielaIcon
Fecha de publicación: 06/2017
Editorial: Elsevier
Revista: Biorganic and Medicinal Chemistry Letters
ISSN: 0960-894X
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Biológicas

Resumen

Dengue is a mosquito-borne virus that has become a major public health concern worldwide in recent years. However, the current treatment for dengue disease is only supportive therapy, and no specific antivirals are available to control the infections. Therefore, the need for safe and effective antiviral drugs against this virus is of utmost importance. Entry of the dengue virus (DENV) into a host cell is mediated by its major envelope protein, E. The crystal structure of the E protein reveals a hydrophobic pocket occupied by the detergent n-octyl-β-D-glucoside (β-OG) lying at a hinge region between domains I and II, which is important for the low-pH-triggered conformational rearrangement required for fusion. Thus, the E protein is an attractive target for the development of antiviral agents. In this work, we performed prospective docking-based virtual screening to identify small molecules that likely bind to the β-OG binding site. Twenty-three structurally different compounds were identified and two of them had an EC50 value in the low micromolar range. In particular, compound 2 (EC50 = 3.1 μM) showed marked antiviral activity with a good therapeutic index. Molecular dynamics simulations were used in an attempt to characterize the interaction of 2 with protein E, thus paving the way for future ligand optimization endeavors. These studies highlight the possibility of using a new class of DENV inhibitors against dengue.
Palabras clave: Anti-Dengue Drugs , Envelope Protein , Molecular Dynamics , Structure-Based Drug Design , Virtual Screening
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Atribución-NoComercial-SinDerivadas 2.5 Argentina (CC BY-NC-ND 2.5 AR)
Identificadores
URI: http://hdl.handle.net/11336/63361
URL: http://www.sciencedirect.com/science/article/pii/S0960894X17306534
DOI: http://dx.doi.org/10.1016/j.bmcl.2017.06.049
Colecciones
Articulos(CIBION)
Articulos de CENTRO DE INVESTIGACIONES EN BIONANOCIENCIAS "ELIZABETH JARES ERIJMAN"
Articulos(IBIOBA - MPSP)
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Articulos(IMIT)
Articulos de INST.DE MODELADO E INNOVACION TECNOLOGICA
Articulos(SEDE CENTRAL)
Articulos de SEDE CENTRAL
Citación
Leal, Emilse Soledad; Aucar, María Gabriela; Gebhard, Leopoldo German; Iglesias, Nestor Gabriel; Pascual, María José; et al.; Discovery of novel dengue virus entry inhibitors via a structure-based approach; Elsevier; Biorganic and Medicinal Chemistry Letters; 27; 16; 6-2017; 3851-3855
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