Although the widespread epidemic of Zika virus (ZIKV), there are still no antivirals available to treat the disease1. Flavonoids from Pterogyne nitens already demonstrated anti-flavivirus activity2. In this study, we screened a database of natural and semi-synthetic compounds against ZIKV NS3 protease and helicase, through virtual screening. We also performed target prediction and validation via biophysical and enzymatic assays. The dockings were performed as part of the OpenZika project3, a collaboration with IBM’s World Community Grid, which accelerates the process distributing the calculations. As a result, we prioritized three flavonoids. Target prediction analysis estimated that protease was the most probable viral target. Enzymatic assays agreed with the in silico predictions, showing that one flavonoid highly inhibited ZIKV protease with IC50 of 3.5 μM. Moreover, two compounds showed activity against ZIKV helicase, IC50 ranged from 17-20 μM. As future steps, we are performing ZIKV cell-based assays to confirm the antiviral activity.