Can I dock ligands with Glide so that the ligand forms a covalent bond with the receptor?

Glide is not designed for docking covalent ligands. It requires that the ligand be a single, isolated molecule, so you must break any bonds to the receptor. You can try using a positional constraint to position the desired ligand atoms near the reactive site on the receptor. However, this is not the same as forming a covalent bond with the receptor.

Instead, we suggest that you try our Prime-based Covalent Docking application, which was added in Suite 2009. You have to specify the receptor bond to break and a SMARTS pattern for the ligand reactive group, and the workflow attaches the ligands to the receptor, optimizing the conformation with Prime. You can set up the job with Applications → Prime → Covalent Docking.

Another possible approach would be to use MacroModel to perform a conformational search on the covalently bound ligand, using substructures to limit the search to the ligand only. With this approach, ranking a series of covalently-bound ligands could be done using energy differences.

Keywords: covalent ligands, docking, Covalent Docking, Glide, Prime

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