In silico analysis of the interaction of pyrimidine derivatives inhibiting the Dengue virus envelope protein E

ADLER, NATALIA S; AUCAR, MARÍA G.; LEAL, EMILSE S.; FERNANDEZ, G.A.; BATTINI, L.; BOLLINI, M.; CAVASOTTO, CLAUDIO N

Buenos Aires

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

Dengue virus is the most prevalent mosquito borne viral pathogen and has become a major public health concern worldwide in recent years. 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. Therefore, the E protein is an attractive target for the development of antiviral agents. In order to identify small molecules that likely bind tothe β-OG pocket, a de novo design approach was used, which  encouraged the pursuit of pyrimidine derivatives. Based on these results, thirty-three 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 (MD) simulations were performed.