Abstract Helicases have emerged as promising targets for the development of antiviral drugs; however, the family remains largely undrugged. To support the focused development of viral helicase inhibitors we identified, collected, and integrated all chemogenomics data for all available helicases from the ChEMBL database. After thoroughly curating and enriching the data with relevant annotations we have created a derivative database of helicase inhibitors which we dubbed Heli-SMACC ( Heli case-targeting SMA ll Molecule C ompound C ollection). The current version of Heli-SMACC contains 20,432 bioactivity entries for viral, human, and bacterial helicases. We have selected 30 compounds with promising viral helicase activity and tested them in a SARS-CoV-2 NSP13 ATPase assay. Twelve compounds demonstrated ATPase inhibition and a consistent dose-response curve. The Heli-SMACC database may serve as a reference for virologists and medicinal chemists working on the development of novel helicase inhibitors. Heli-SMACC is publicly available at https://smacc.mml.unc.edu . Highlights We created a curated Helicase-Targeting SMAll Molecule Compound Collection (Heli-SMACC). Heli-SMACC covers 29 human, viral, and bacterial helicases. Twelve of thirty selected compounds demonstrated inhibitory activity in a SARS-CoV-2 NSP13 ATPase Assay. Heli-SMACC is freely available online at https://smacc.mml.unc.edu . TOC Graphic

Heli-SMACC: Helicase-targeting SMAll Molecule Compound Collection