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How can I account for binding site flexibility?

The receptor atoms are fixed during Glide docking. To reduce false negatives, Glide permits some ligand strain in fitting the ligand into the rigid active site, and also allows scaling of the van der Waals radii of non-polar receptor and ligand atoms. By default the scalings are 1.0 and 0.8 for the receptor and ligand, respectively. If you are working with a particularly tight active site, you could try reducing these scaling factors to allow non-native ligands to dock and score better.

Note that changing the scaling factors changes the scores, so results from runs with different scalings cannot be compared directly. Also, as a general rule, it is a good idea to test adjusted scalings on a set of known actives in order to determine the optimal settings before trying a full virtual screening run.

Glide also allows sampling of hydroxyl group orientations in the receptor, which you can enable when you generate the grid. The hydroxyl group orientations are varied during docking to generate poses with different orientations.

If the receptor is known to undergo significant side-chain motion during binding of ligands, you should try Induced Fit Docking (IFD). IFD generates new complexes by optimizing active-site side chains in the presence of possible ligand poses. If there are side chains that would prevent the generation of good initial poses (e.g., a bulky side chain swinging into the active site in the apo form), you can mutate selected residues to ALA for the initial docking stage.

IFD primarily explores side-chain motion, though the receptor backbone can move a bit during the Prime optimization stage, which includes both side-chain rearrangement and minimization of the active site. If larger backbone motions are expected, you might try adding a Loop Refinement stage to the IFD input file and run the job from the command line, as described in the Induced Fit Docking manual.

Keywords: Glide, IFD, induced fit, binding site, flexibility

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