HYBRID Theory

HYBRID docks multiconformer molecules into one or more receptors with bound ligands using an exhaustive search that systematically searches rotations and translations of each conformer of the ligand within the active site. Following the exhaustive search the top scoring poses are optimized and assigned a final score. These two steps are described in more detail below

Receptor Selection

Note

If there is only one receptor this these steps are skipped and all ligands are docked to the receptor.

  1. For each ligand in the docking database the similarity of the ligand to each of the receptor’s bound ligands is calculated based on the 3D shape and chemical similarity of the docking ligand and bound ligand.

  2. Each ligand is then docked to the single receptor that has the most similar bound ligand as described in the following steps.

Exhaustive Search

  1. Enumerates, to given resolution, every possible rotation and translation of each conformer of the ligand being docked within a box enclosing the active site. The resolution of the exhaustive search is determined by the overall resolution setting of -dock_resolution flag.

  2. Discard poses that either clash with the protein or extend to far from the binding site using the receptor’s negative image outer contour (see Negative Image section).

  3. If the negative image inner contour is enabled discard any poses that do not have at least one heavy atom that falls within the inner contour. (see Negative Image section).

  4. Discard any poses that do no match any user specified constraints. (see Constraints section).

  5. Score all remaining poses using Chemical Gaussian Overlay.

  6. Sort poses by score and pass the top scoring poses to optimization.

Optimization

  1. Enumerate nearby positions of each pose by having the initial pose take one positive and one negative step for each translational and rotational degree of freedom (729 poses total). The resolution of these steps is half that of the exhaustive search, and is determined by the setting of the -dock_resolution flag.

  2. Each pose is scored with Chemgauss4.

  3. The best scoring poses are retained. The number of poses retained is determined by the setting of the -num_poses parameter.

  4. The overall score of the molecule, used to rank the molecule against other molecules in the docking database, is set to the best scoring pose’s score.