Fig. 6: Fragments provide merging opportunities that lead to on-scale potency.

a Fragments selected as parent hits for rapid follow-up compound design. Fragment alignment shows opportunities for merging and linking. b Predicted mergers posed in the active site. The 2D structure is shown at the top with its Enamine compound identity code. RMSD value indicates the conformational variance of its parent fragments. Fragments are shown in thin sticks, predicted mergers are shown in sticks and spheres. c A crystal structure of ASAP-0022538 bound to ZIKV NS2B-NS3 (PDB ID: 7I9O) is shown as an example of a merge design that achieves on-scale activity (low double-digit micromolar IC₅₀). ASAP-0022538 recapitulates the poses and interactions of fragments x0089, x1098 and x0404, exhibiting an IC₅₀ value of 14.2 µM. Water molecules are shown as red spheres. Hydrogen bonds and electrostatic interactions are shown as black and orange dashed lines, respectively. Aromatic stacking interactions are shown as titled lines. Omit map of ASAP-0022538 is shown in Supplementary Fig.5. The IC₅₀ plot is shown as representative data from three independent experiments with consistent results (Source Data- Fig. 6c). Error bars in the IC₅₀ plot indicate standard deviations (SD) from technical duplicates in one experiment. Source data are provided as a Source Data file.