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Article ID: 738 - Last Modified: June 6, 2011

I have two receptor structures: one is a crystal structure in the open conformation with iron and cofactor only, the other is a model in the closed conformation with both iron, solvent (which occupies the cofactor position) and substrate. The difference between the two structures is the flap region opening or closing. How should I go about finding inhibitor candidates with Glide?

The answer probably depends on the operation of the receptor and inhibitors. It also depends on if you are looking for cofactor-competitive inhibitors, substrate-competitive inhibitors, or both.

For cofactor-competitive inhibitors, you could use the open cofactor structure, picking the cofactor during grid generation setup so it is removed (to make room for ligands to dock).

For substrate-competitive inhibitors, you could use the closed substrate structure, picking the substrate as the ligand. You also could try docking to the open structure, but retaining the cofactor (i.e., searching just the substrate pocket); if the substrates interact directly with the cofactor, this might be an important case to consider.

To allow for inhibitors that span the cofactor and substrate pockets (if possible), you could try setting the grid center and size such that the whole active site can be explored.

If the iron bound to the receptor (in addition to being bound to the cofactor/substrate), has a consistent position in the two structures you should leave it in the receptor structure during docking. This means you'll have to break any zero-order bonds between the iron and the molecule you pick as the ligand during Grid Generation.

If you don't have a crystal structure with both the cofactor and the substrate, it might be that the absence of the cofactor has affected the receptor conformation in the substrate-only crystal structure. You could consider using IFD to generate a receptor conformation with both the cofactor and the substrate, and then use that for docking. If the substrate is a small molecule, you probably should use the open cofactor structure as the starting structure for IFD (fitting in the substrate). If the substrate is a large, flexbile molecule (e.g., a peptide), it might be better to start IFD with the substrate-only structure (fitting in the cofactor).

To have the most general search for inhibitors, you could use VSW to dock your ligand library to more than one of the structures mentioned above.

Keywords: cofactor, inhibitor, substrate, Glide, VSW

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