In CACHE #2, computational teams were challenged to find drug-like ligands targeting the RNA-binding site of the SARS-CoV-2 helicase Nsp13, a site with bound fragments in the PDB (PDB codes 5RLH, 5RLZ, 5RML, and 5RMM) (Figure ). The reported fragments had no measurable binding affinity but highlighted putative interaction hotspots in the RNA binding site of Nsp13, which is one of the two most conserved sites in the coronavirus proteome and represents an attractive target for novel antivirals . Nucleic acid binding sites are typically highly polar and poorly druggable, but low micromolar ligands targeting the RNA sites of SNRNP200 and HCV NS3 (PDB 5URM and 4OKS, respectively) have been reported, supporting the idea that these sites can successfully be targeted by small molecules in some cases. Helicases are a clinically validated target class but are often recalcitrant to medicinal chemistry efforts due to the transient nature of their conformational states . As such, well-characterized small molecule ligands for Nsp13 would represent valuable chemical starting points for drug discovery. image formed by superimposing experimental structures of Nsp13 in complex with four fragments and in complex with RNA and ADP (blue and orange respectively; PDB code 7RDY ). CACHE #2 participants were asked to find ligands targeting the RNA-binding site occupied by fragments. Electrostatic potential coloring of the binding site, revealing the overall polar area, and bound fragments are depicted in the inset.