IN SILICO STRUCTURE-BASED DESIGN OF NOVEL INHIBITORS TARGETING THE DENGUE VIRUS ENVELOPE PROTEIN E

LEAL, EMILSE S.; BOLLINI, MARIELA; AUCAR, MARÍA GABRIELA; BATTINI, LEANDRO; ADLER, NATALIA S.; FERNANDEZ, GABRIELA A.; CAVASOTTO, CLAUDIO N.

Ciudad Autónoma de Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018; 2018

Facultad de Farmacia y Bioquímica - Universidad de Buenos Aires

Dengue virus is the most prevalent mosquito-borne viral pathogen and has become a major public health concern worldwide in recent years. It is, at present, endemic in over a hundred countries around the world.1 However, no clinically approved antiviral therapy is available, so multiple efforts are being made by both industry and academia to develop anti dengue virus agents.The entry of the virus into the host cell is mediated by its major envelope protein, E. The crystal structure of this 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.2 Therefore, the E protein is an attractive target for the development of antiviral agents.In a previous work3, we performed prospective docking-based virtual screening to identify small molecules that likely bind to the β-OG binding site. In this work, a de novo design approach was used, which encouraged the pursuit of pyrimidine and quinazoline derivatives. Based on this results, forty-two compounds were synthesized and their antiviral activity evaluated using a luciferase-expressing dengue reporter virus assay. All but three of them showed activity in the low micromolar range.To further characterize the likely interaction between the new molecules and the E protein, molecular docking of selected hits and molecular dynamics simulations were performed. Thus, we were able to determine key features needed in a molecule to correctly exercise its antiviral activity.References:1-G.N. Malavige, S. Fernando, D.J. Fernando, S.L. Seneviratne, Dengue viral infections,Postgrad. Med. J. . 80 (2004) 588?601. doi:10.1136/pgmj.2004.019638. 2-Y. Modis, S. Ogata, D. Clements, S.C. Harrison, A ligand-binding pocket in the dengue virus envelope glycoprotein, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 6986?6991. doi:10.1073/pnas.0832193100.3-E. S. Leal, M. G. Aucar, L. G. Gebhard, N. G. Iglesias, M. J. Pascual, J. J. Casal, A. V. Gamarnik, C. N. Cavasotto, M. Bollini, Discovery of novel Dengue virus entry inhibitors via a structure-based approach, Bioorg. Med. Chem. Lett. 27 (2017) 3851-3855. doi.org/10.1016/j.bmcl.2017.06.049