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

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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2017 vol. 27 p. 3851 - 3855

0960-894X

P { margin-bottom: 0.08in; direction: ltr; color: rgb(0, 0, 0); widows: 2; orphans: 2; }P.western { font-size: 12pt; }P.cjk { font-size: 12pt; }P.ctl { font-size: 12pt; }A:link { color: rgb(5, 99, 193); }Dengue is a mosquito-borne virusthat has become a major public health concern worldwide in recentyears. However, the current treatment for dengue disease is onlysupportive therapy, and no specific antivirals are available tocontrol the infections. Therefore, the need for safe and effectiveantiviral drugs against this virus is of utmost importance. Entry ofthe dengue virus (DENV) into a host cell is mediated by its majorenvelope 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, which is important for the low-pH-triggeredconformational rearrangement required for fusion. Thus, the Eprotein is an attractive target for the development of antiviralagents. In this work, we performed prospective docking-based virtualscreening to identify small molecules that likely bind to the β-OGbinding site. Twenty-three structurally different compounds wereidentified and two of them had an EC50 value in the lowmicromolar range. In particular, compound 2 (EC50 =3.1 μM) showed marked antiviral activity with a good therapeuticindex. Molecular dynamics simulations were used in an attempt tocharacterize the interaction of 2 with protein E, thuspaving the way for future ligand optimization endeavors. Thesestudies highlight the possibility of using a new class of DENVinhibitors against Dengue.