Discovery of novel dengue virus entry inhibitors via a structure-based approach.
Leal, E. S., Aucar, M. G., Gebhard, L. G., Iglesias, N. G., Pascual, M. J., Casal, J. J., Gamarnik, A. V., Cavasotto, C. N. and Bollini, M.
Laboratorio de Quimica Medicinal, Centro de Investigaciones en Bionanociencias (CIBION)-CONICET, Godoy Cruz 2390, Ciudad de Buenos Aires, Argentina.
Laboratory of Computational Chemistry and Drug Design, Instituto de Investigacion en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Godoy Cruz 2390, Ciudad de Buenos Aires, Argentina; Instituto de Modelado e Innovacion Tecnologica, CONICET, and Departamento de Fisica, FCENA-UNNE, Avda. Libertad 5460, Corrientes, Argentina.
Fundacion Instituto Leloir-CONICET, Av. Patricias Argentinas 435, Ciudad de Buenos Aires, Argentina.
Instituto de Investigaciones Biotecnologicas, Universidad Nacional de San Martin, CONICET, Av. 25 de Mayo y Francia, San Martin, Prov. de Buenos Aires, Argentina.
Laboratory of Computational Chemistry and Drug Design, Instituto de Investigacion en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Godoy Cruz 2390, Ciudad de Buenos Aires, Argentina. Electronic address: cnc@cavasotto-lab.net.
Laboratorio de Quimica Medicinal, Centro de Investigaciones en Bionanociencias (CIBION)-CONICET, Godoy Cruz 2390, Ciudad de Buenos Aires, Argentina. Electronic address: mariela.bollini@cibion.conicet.gov.ar.
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-beta-d-glucoside (beta-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 beta-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=3.1muM) 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.
Bioorganic and Medicinal Chemistry Letters 27(16): 3851-3855 (2017)