Inclusion of Shape Information

One of the most prominent reasons for the retrieval of false-positives in pharmacophore screens is the lack of spatial restriction of the models the chances that a compound will have the required features somewhere present in its structure increases with its size and flexibility. Therefore, most 3D pharmacophore methods have the possibility to add either inclusion or shape volumes that must be filled by the ligands, or forbidden or excluded volumes that describe the space that is occupied by atoms forming the binding site. 

In structure-based pharmacophore modeling, excluded volume spheres can be placed at atoms forming the binding site, a feature that has also been included in LigandScout. For faster screening and less restrictive models, LigandScout alternatively allows for the placement of only a few excluded volume spheres at the lipophilic side-chain residues that are in contact with hydrophobic features in the ligand. We have found that excluded volume 

An explicit specification of inactive compounds as well as the maximum number of excluded volume spheres, and softening of excluded volume spheres during fitting can be adjusted by the user. 

Even with quantitative models that have been generated with the upmost care to the guidelines given above, affinity prediction can often be off by two or more orders of magnitude for certain compounds. It has thus become a widely-used 

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