Classical and quantum mechanical simulations exploring the interaction between entry inhibitors and protein E of dengue virus

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

Congreso; XLII Congress of the Brazilian Biophysics Society (SBBf); 2017

Dengue is amosquito-borne virus that has become a major public health concern worldwide inrecent years. However, the current treatment for dengue disease is onlysupportive therapy, and no specific antivirals are available to control theinfections. Therefore, the need for safe and effective antiviral drugs againstthis virus is of utmost importance. Entry of the dengue virus (DENV) into ahost cell is mediated by its major envelope protein, E. The crystal structure of the E protein reveals a hydrophobicpocket occupied by the detergent n-octyl-β-D-glucoside (β-OG) lying at a hingeregion between domains I and II, which is important for the low-pH-triggeredconformational rearrangement required for fusion. Thus, the E protein is an attractive target forthe development of antiviral agents. We performed prospective docking-basedvirtual screening to identify small molecules that likely bind to the β-OGbinding site. Twenty-three structurally different compounds were identified andtwo of them had an EC50 values in the low-micromolar range. Inparticular, compound 2 (EC50= 3.1 μM) showed marked antiviral activity with a good therapeutic index.Molecular dynamics simulations, followed by classical and quantum mechanicalestimation of the binding free energy were used in an attempt to characterize the interaction of 2 with protein E, thuspaving the way for future ligand optimization endeavors. These studieshighlight the possibility of using a new class of DENV inhibitors againstDengue.