A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13...

Herein we report the in silico discovery of 13 novel micromolar potent inhibitors of the SARS-CoV-2 NSP13 helicase validated in cellular antiviral and biophysical ThermoFluor assays. The compounds, discovered using a novel fragment-based pharmacophore virtual screening workflow named FragmentScout, enable the advancement of novel antiviral agents. FragmentScout uses publicly accessible structural data of the SARS-CoV-2 NSP13 helicase, which was previously generated at the Diamond LightSource by XChem high-throughput crystallographic fragment screening. The workflow generates a joint pharmacophore query for each binding site, thereby aggregating the pharmacophore feature information present in each experimental fragment pose. The joint pharmacophore query is then used to search 3D conformational databases using the Inte:ligand LigandScout XT software. The FragmentScout in silico workflow offers a novel tool for identifying micromolar hits from millimolar fragments in fragment-based lead discovery. It is anticipated that this workflow will enhance systematic data mining of the growing collection of XChem datasets.