Dual structure-based approach towards the design of inhibitors of the Dengue virus envelope protein

LEAL, EMILSE S.; AUCAR, MARÍA G.; GEBHARD, LEOPOLDO G.; PASCUAL, MARÍA J.; GAMARNIK, ANDREA V.; CAVASOTTO, CLAUDIO N.; BOLLINI, MARIELA

Munich

Congreso; 11th Triennial Congress of the World Association of Theoretical and Computational Chemists; 2017

P { margin-bottom: 0.1in; direction: ltr; color: rgb(0, 0, 10); line-height: 120%; widows: 2; orphans: 2; }P.western { font-family: "Calibri",sans-serif; font-size: 11pt; }P.cjk { font-family: "Calibri",sans-serif; font-size: 11pt; }P.ctl { font-family: "Calibri",sans-serif; font-size: 11pt; }Dengueis a mosquito-borne viral disease that has become a major publichealth concern worldwide in recent years. At present, dengue isendemic in many popular tourist destinations in Latin America,Southeast Asia and the Pacific islands.However, no clinically approved antiviral therapy is available. Thefirst dengue vaccine has been recently approved and licensed in sixcountries, but it was reported to be 60% effective and not togenerate immunity against all serotypes reported. To satisfy thisunmet medical need for an antiviral therapy, both industry andacademia have taken multiple approaches to develope anti dengue virusagents. Entry of the dengue virus into a host cell is mediated by itsmajor envelope protein, E.The crystal structure of the Eprotein reveals a hydrophobic pocket occupied by the detergentn-octyl-β-D-glucoside (β-OG) lying at a hinge region betweendomains I and II. Therefore, the E protein is an attractive target for the developmentof antiviral agents. We used in silicostructure-based virtual screening and denovo design approaches to identifysmall-molecules that likely bind to the β-OG binding site.Twenty-three structurally different compounds were selected fromdocking-based virtual screening and ten compounds emerging from denovo design were synthesized. Theantiviral activity of the compounds was evaluated using an assaybased on a luciferase-expressing denguereporter virus. Six compounds showedantiviral activity in the 3-10 μM rangeand displayed a good therapeutic index. Based on their antiviralpotency and selectivity, these compounds will be subject of a moredetailed and elaborate virological study to gain insights into theprecise molecular mechanism of action.