Creating Structure-Based Pharmacophores
Data Import and Structure Preparation
For the automated generation of pharmacophore models, please
import
your favored PDB complex to the Structure-Based Modeling Perspective in LigandScout. Since PDB data does not
provide information on atom hybridization states and bond types,
LigandScout uses a sophisticated ligand interpretation algorithm
for the assignment of bond types via molecular geometry analysis.
Data quality of PDB ligands is known to be an issue in molecular
modeling. Therefore, manual verification of the automatically
deduced ligand structure is highly recommended. Moreover, it
represents a vital verification step for the subsequent
pharmacophore generation process. Special care should be taken on
double bond types and also on tautomerism.
Tautomers
are not
discriminated by geometric analysis but have a decisive impact e.g.
on hydrogen bond features.
As you have imported and verified your macromolecule-ligand
structure, you are ready to run LigandScout's automated
pharmacophore generation procedure. Please note that structure-based pharmacophore
generation is only available in
Active Site View
.
Automated Generation of Structure-Based Pharmacophores
In
Active Site View
,
simply press F9 on your keyboard to start the
analysis. Alternatively, you may also use the
Create Pharmacophore
button or through the menu
>
. LigandScout will
calculate the pharmacophore model within seconds.
LigandScout is designed for the retrieval of automatically
created advanced 3D pharmacophore models supporting multiple
features per heavy atom to broaden the scope of a single model.
However, not all external in-silico screening applications support
the wealth of pharmacophore feature handling which is incorporated
into LigandScout.
If you are using the software-packages Catalyst, MOE or Phase
it is recommended to use the
Create Simplified
Pharmacophore
routines to achieve best compatibility to
these external software applications.
You may also edit advanced pharmacophores for analysis using
Catalyst, MOE or Phase by manually deleting features. In this case, it is
recommended to first delete features interacting with water
molecules and then to erase features that have unfavorable
distances and angles. Try to obtain the best feature(s) for every
heavy atom. You can use literature to prioritize interactions.
Tutorials on pharmacophore preparation for
Catalyst
,
MOE
, and
Phase
provide
more detailed information on this issue.
Please note that simplified pharmacophores are less
restrictive and do not represent LigandScout's full capacity of
pharmacophore generation.
Creating Advanced Structure-Based Pharmacophore Models
LigandScout supports several additional pharmacophore
generation modes. More detail is provided
here
.
Creating Excluded Volumes Coat
LigandScout supports the generation of an excluded volume
coat for structure-based pharmacophore models via the menu
>
. Especially in the case of
tight binding pockets, this approach allows one to significantly enhance
the selectivity of the model. However, it is also well-suited for
the simulation of binding cavities on the protein surface.
Creating Pharmacophore Models from Injected Ligands
Ligands can be injected into different context:
binding pocket, solely ligand or pharmacophore.
In the
Active Site View
you can add ligands from external sources by inserting a
file containing molecules by the menu
>
. The external ligands have to be in the
correct coordinate frame to yield a meaningful result. For
instance, if the molecule to be injected was docked into the active
site before, this restriction will be fulfilled. If the coordinate
frame was not correct, the inserted ligand will be placed into the
coordinate frame of the active site no matter if it makes sense or
not.
In this way you can create pharmacophore models based on a
certain docking pose for rapid virtual screening of novel leads.
Another application of this feature is the investigation
of docking poses, since it allows you to simply visualize the
protein-ligand interactions of these conformers by generating the
pharmacophore model.
If the external ligands are not in the coordinate frame,
you can align them into the context.
For more information on that, please see
the section called “Library View”
which
enables you to navigate quickly through large compound collections.
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