Heli-SMACC: Helicase-targeting SMAll Molecule Compound Collection

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 (Helicase-targeting SMAll Molecule Compound Collection). 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.

Keywords: Antiviral Drug Discovery; Database; Drug Repurposing; Helicases; Viral Helicase Inhibitors.

Figure 1.

Summary of active and inactive human, viral, and bacterial helicase assay results in Heli-SMACC. A) Number of unique helicases present in each organism. B) Number of compounds tested across each helicase organism. C) Distribution of active and inactive assay results per organism. D) Number of entries present per helicase super family. E) Number of entries represented for DNA and RNA helicases.

Figure 2.

A) Distribution of compounds tested against human, viral, and bacterial helicases in chemical space. The two major clusters are highlighted, corresponding to the data color for the human (green), viral (orange), and bacterial (blue) helicase data. B) Representative molecules from the top clusters of compounds tested against human, viral, and bacterial helicases.

Figure 3.

A) The number of compounds tested against helicases in superfamilies one through four. B) Distribution of compounds tested against each helicase superfamily in chemical space. The top clusters are highlighted in the corresponding data color for superfamilies one (dark blue), two (red), three (purple), and four (light green). C) Representative molecules from the top clusters of compounds tested super families one through four.

Figure 4.

A) Distribution of compounds with reported helicase activity in chemical space. Grey coloring indicated chemical similarity to nearest neighbor <0.8, whereas a coloring scale from red to green indicated >0.8 similarity between nearest neighbors. The five major clusters of highly similar compounds are highlighted in black. B) Representative molecules from the top five clusters.

Figure 5.

Examples of viral RNA helicase inhibitors nominated for experimental testing. The upper left cell defines the tables contents.

Figure 6.

Dose-response of selected helicase inhibitors in NSP13 ATPase assay (kinase-glo). The Y-axis shows the % Activity, and the X-axis shows the concentration of each compound.