How do I prepare and use a cofactor-containing receptor for Glide docking?

The Protein Preparation Wizard will prepare any cofactors and/or cocrystallized ligands along with the protein receptor, including the addition of hydrogens and higher-order bonds, generation of ionization or tautomeric states, H-bond network optimization, and constrained refinement.

Next, you must decide whether to include the cofactor as part of the rigid receptor during Glide docking. If you are searching for ligands that will displace the cofactor, then you should remove the cofactor from the receptor structure. On the other hand, if you are searching for ligands that displace only the co-crystallized ligand, but bind to the cofactor, then the cofactor should be retained as part of the rigid receptor structure. For the most general ligand screening, you can dock to receptor structures with and without the cofactor present. Grids must be generated for each version of the receptor, and ensemble docking to both models can be done with the Virtual Screening Workflow.

During Grid Generation, only a single molecule can be picked as the ligand. If there is no cocrystallized ligand and you want to remove the cofactor from the receptor structure, pick the cofactor as the ligand. Note, though, that the other purpose for picking the ligand is to allow the grid box center and size to be set according to that ligand. This might not be appropriate when a cofactor is picked as the ligand. You can use the alternative methods for defining the grid box parameters on the Site tab instead.

If there is a cocrystallized ligand present, and you want to remove both the ligand and the cofactor from the receptor structure, you'll have to remove one of the molecules manually (e.g., duplicate the entry in the Project Table, and then delete the cofactor molecule in the new entry). Then, you can pick the other molecule as the ligand during Grid Generation setup to remove it from the receptor structure.

If the cofactor is retained in the receptor structure during docking, it is treated rigidly. If the cofactor conformation is expected to change upon binding different ligands, then additional receptor (with cofactor) models could be generated (e.g., with IFD or MacroModel conformational searches) for ensemble docking.

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