Extended Data Fig. 5: In silico docking of GHP-88309.

In silico docking of GHP-88309. a, Ribbon representation of the MeV L internal channel, showing distances between confirmed resistance sites (red) and the nearest residue in photoaffinity labeled peptide 3 (D993; black). Polymerase domain color-coding as in Fig. 2a. b, Docking of GHP-88309 (blue sticks) and GHP-88309-016 (yellow sticks) into the MeV L model, using D993 and confirmed resistance hot-spots as target site guides. The top-scoring pose is conserved between GHP-88309 and GHP-88309-016, and positions the between capping and RdRP domains. The aryl-azide moiety is located approximately 7.8 Å from residue D993 in peptide 3. Numbers denote predicted free energy associated with this docking pose. c, 2D-diagram of predicted top-scoring ligand interaction generated with MOE. Predicted are hydrogen bond interactions between the isoquinoline ring of GHP-88309 and residues Y942 and R865. The benzamide moiety is posited between residues Q1007 and R1011, thus overall linking RdRP and capping domains. d, e, Application of the equivalent in silico docking approach as in (b) to NiV (d) and RSV L (e). Top scoring poses in NiV (pink sticks) and RSV (white sticks) L are distinct from that in MeV L (superimposed as blue sticks). Known resistance mutations are colored red (a-b, d, e). NiV homology model is based on HPIV5 L (PDB: 6v85); RSV L is native (PDB: 6pzk).