Find potential binding pockets
A molecular docking is aimed at a specific region of the target protein, expected to be the binding site. You may know the location of this site based on the position of ligands or cofactors co-crystallized with the protein structure, or positions of amino acids known to participate in the binding. If you don't know the binding site, you can use the "Find Binding Pockets" tool to search for cavities on the protein surface.
To run the "Find Binding Pockets" tool:
Toolbox | Drug Design (
) | Find Binding Pockets (
)
This will open up the wizard that allows you to specify the Molecule Project holding the target protein that should be used as input.
Note! All protein chains in the Molecule Project will be considered in the evaluation, and protein chains, which are not biologically relevant (e.g. crystal packing units), should therefore be deleted before the search for binding pockets is initiated.
Click on the button labeled Next.
Figure 10.62: Parameter settings in the Find Binding Pockets tool.
In the wizard step 2 (figure 10.62), the following parameters can be adjusted:
- Find binding pockets settings
- Ignore pockets with volumes (Å3) less than. Pockets with volume below the given threshold are ignored. Analysis of 5600 protein-ligand structures from the PDB has revealed that 95 % of binding sites are within one of the three largest solvent-accessible pockets found on the protein [Li et al., 2008]. Typically, it is therefore only relevant to look at the largest pockets, and the smaller pockets can safely be ignored.
- Include more exposed pockets. Per default, only compact pockets will be found. Enabling this option will include more exposed pockets in the search. Pockets with good drug-binding properties are typically compact, but not always[Cheng et al., 2007a], and it can therefore sometimes be relevant to look for the more exposed pockets too.
Click on the button labeled Finish. After a while, binding pockets appear in the Project Tree of the Molecule Project that was used as input. You can use the check boxes in the Project Tree to display the identified binding pockets one by one. This is shown in figure 10.63.
Figure 10.63: Binding pocket indicated with green spheres.
Note! If no pockets are found, a notification will appear in the workbench, and nothing will be added to the Project Tree. You can increase the chances of finding pockets by decreasing the volume limit for when a pocket is ignored, or include more exposed pockets.
Subsections