Therapeutic targeting of measles virus polymerase with ERDRP-0519 suppresses all RNA synthesis activity
Fig 6
In silico docking and ERDRP-0519 pharmacophore extraction.
A) Top view of the RdRP (cyan) and capping (green) domains of MeV L. PRNTase motifs, ERDRP-0519 resistance mutations, and ERDRP-519 are shown as blue, black, and magenta spheres, respectively. Peptide 2 (purple), the priming loop (red) and intrusion loop (blue) are labeled. The top scoring docking pose places ERDRP-0519 (orange) in close proximity to peptide 2. B) 2D-interaction projection of the top scoring ERDRP-0519 docking pose. The sulfonyl oxygen is predicted to interact with H1288 of the HR motif and the pyrazol ring hydrogen bonds with Y1155 of peptide 2. C-D) The binding pocket of ERDRP-0519 is not available in an MeV L homology model based on VSV L in initiation conformation (PDBID: 5A22) (C). Attempts to insert ERDRP-0519 result in multiple steric violations (moieties of the compound structure highlighted in red) (D). E-G) Close-up view (E), 2D-interaction map (F), and scaffold overlays (G) of the corresponding top-scoring covalent ERDRP-0519az docking pose. Positioning and main scaffold orientation resembles the pose of ERDRP-0519, although the sulfonyl group hydrogen bonds with D1378 instead of H1288. The lateral ring system containing the azide moiety of ERDRP-0519az (yellow sticks) must rotate (G) to fit.