Can I use Glide to score poses produced by Prime Covalent Docking?

Yes. Scoring covalent complexes with Glide remains an area of open investigation for us, but our current recommendations are

Please note, this method works best when you start with a covalent ligand-receptor complex where the starting covalent ligand is similar to the ligand(s) you plan to dock.

1) Start by deleting the covalent bond between the ligand and receptor.

2) Remove a constant reactive warhead off the ligand* or truncate the receptor side chain (e.g., by mutating to Ala or Gly) to avoid clashes introduced by deleting the covalent bond between the ligand and receptor. Since the ligand and/or receptor structures are being modified, concerns about the validity of the scores produced by Glide could be raised. However, since the part of the ligand binding to the receptor is often the same across a set of covalent ligands, any artifacts introduced by these modifications should be roughly constant across the ligands of interest, allowing meaningful comparisons.

*If you are removing a constant reactive warhead from a congeneric ligand series, you should make the same atom deletions for the whole ligand series. You can do this in Maestro:

       I) align the ligand series (by flexible ligand alignment or superposition)
       II) include all the ligands in the Maestro workspace
       III) drag-select the atoms to delete
       IV) right-click and choose Delete
       V) add hydrogens to any truncated ligand

3) Set up a positional constraint (during Grid Generation) or core constraint (during Ligand Docking) to ensure that the covalent attachment point of the ligand remains close to the desired location in the active site.

4) Turn off post-docking minimization (on the Output tab of the Ligand Docking panel), because in the current release, that feature doesn't strictly honor constraints.

5) Run Glide in "Refine (do not dock)" mode to generate a good pose similar to the input pose. Since you're modifying both the ligand and receptor structures, it is good to allow some relaxation of the ligand pose in the active site, which a "Score in place (do not dock)" job wouldn't permit. If you want Glide to sample the ligand conformations (subject to the covalent-attachment constraint), you could run a flexible docking job rather than a refine-only job.

Keywords: covalent docking, Prime, scoring, rank ordering

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