Despite the recent outbreak of Zika virus (ZIKV) in the Americas and the global concern that it has raised, there are still no approved drugs to treat the infection. We describe here an open collaborative project called OpenZika with IBM’s World Community Grid, which uses distributed computing on millions of computers to run virtual screening experiments, in order to dock millions of compounds against ZIKV proteins (and other related Flavivirus targets). From May 2016 to March 2018, we submitted 4.4 billion docking calculations and received almost 4.3 billion results. Subsequently, we developed machine learning (QSAR) models with phenotypic data for ZIKV, aiming to help the final selection of compounds for <i>in vitro</i> testing. We will describe our computational efforts focused on several Zika proteins. The first target screened was NS3 helicase (NS3h), a promising target for antiviral drug discovery due to its essential role in the replication of the viral genome. We initially screened the ~ 8,000 compounds in the ZINC library of approved drugs (US & EU) + the NIH clinical collection. The compounds passed through energetic, interaction-based docking and QSAR filters. The predicted binding modes of promising compounds were inspected in detail. Six of the eight compounds selected have been validated using biochemical assays (ATPase activity and thermal stability assays with ZIKV NS3h) and showed promising results. Afterwards, the ChemBridge database (~1,000,000 compounds) was virtually screened against NS3h and the selected virtual hits are being experimentally validated. Moreover, we have performed docking calculations with 13 natural products extracted from <i>Pterogyne nitens</i>, which showed activity against the Hepatitis C Virus replication cycle and presented anti-ZIKV effects, to predict their potential ZIKV targets and to shed some light into their mechanism of action. Some of the studied natural compounds presented good docking results against specific ZIKV proteins and are being validated through enzymatic assays. All the docking data is being made openly accessible so that all members of the global research community can use them to further advance drug discovery studies against ZIKV.

OpenZika: Discovery of new antiviral candidates against Zika virus

256th National Meeting (2018)

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