Subsections

6.6 Ligand+Structure based design

Two of FRED's scoring functions, CGO and CGT, are ligand based design scoring functions. That is they score by measuring how well a pose matches a known bound ligand in the active site, rather than measuring how well the ligand interacts with the site itself. By using these two functions you can then do ligand based design with FRED, or even more interestingly you can combine both ligand and structure based design by using a combination of the structure based and ligand based scoring functions. This section has several examples of using the ligand based design scoring functions.

Note that even when all the docking and scoring functions are ligand based design functions (i.e. CGO or CGT) information from the protein is still used during the exhaustive search to screen the initial ensemble of poses using the inner and outer contour, as well as any constraints. In other words when you use CGO and CGT FRED will still insure that the poses do not clash with the ligand and obey any constraints the user has specified.

6.6.1 Scoring with ligand based design

6.6.1.1 Command Line

fred -dbase my_ligands.oeb.gz \
     -rec my_receptor.oeb.gz \
     -cgo \
     -cgt

6.6.1.2 Description

FRED will dock my_ligands.oeb.gz to my_receptor.oeb.gz and then score and output the resulting poses to a CGO and CGT hitlist.

The docking process is still structure based in this example, only the final scoring in ligand based. See the next example for how to do structure based docking and scoring.

Note that CGO and CGT are treated the same as any other scoring function by FRED, provided the receptor has a bound ligand.

6.6.1.3 Parameters

-dbase

my_ligands.oeb.gz

This tells FRED where the ligands it is going to dock are, in this case the file my_ligands.oeb.gz. The ligand file should have multiple conformers of all flexible ligands (see section 5.5 for more detail on preparing the ligand database).

-rec

my_receptor.oeb.gz

This specifies a receptor file to dock the ligand to. The receptor file must be created prior to running FRED with this command line, and it must contain a bound ligand.

-cgo

Tells FRED to score with CGO.

-cgt

Tells FRED to score with CGT.

6.6.1.4 Output

setup.txt: A file with the settings of all of FRED's parameters. Note that there will be many more parameters in this file than those specified on the command line because many parameters have default values. This file will be written at the beginning of the run.
receptor.oeb.gz: This file contains a copy of the receptor site used for the run. This file will be written at the beginning of the run.
status.txt: This file will be written every few seconds by FRED and indicates the status of the run.
cgo_docked.oeb.gz: contains the structure of the top 1000 docked ligands as ranked by CGO.
cgo_scores.txt: list the names, scores and SMILES representation of the top 1000 docked ligands as ranked by CGO in a text format.

6.6.2 Docking and scoring with ligand based design

6.6.2.1 Command Line

fred -dbase my_ligands.oeb.gz \
     -rec my_receptor.oeb.gz \
     -exhaustive_scoring cgo \
     -opt cgo \
     -pose_select_weight_shapegauss 0 \
     -pose_select_weight_plp 0 \
     -pose_select_weight_Chemgauss2 0 \
     -pose_select_weight_Chemgauss3 0 \
     -pose_select_weight_Chemscore 0 \
     -pose_select_weight_oeChemscore 0 \
     -pose_select_weight_screenscore 0 \
     -cgo \
     -cgt

6.6.2.2 Description

This command line tells FRED to docking my_ligands.oeb.gz to my_receptor.oeb.gz using the ligand based CGO scoring function and then score and output the ligands to CGT and CGO hitlists. Consensus structure is also disabled since the purpose of this example is to maximize the amount of ligand based design, and there is only one scoring function for consensus structure that is ligand based, CGO.

6.6.2.3 Parameters

-dbase

my_ligands.oeb.gz

-rec

my_receptor.oeb.gz

This specifies a receptor file to dock to the ligand too. The receptor file must be created prior to running FRED with this command line, and it must contain a bound ligand.

-exhaustive_scoring

cgo

Tells FRED to use CGO as the scoring function in the exhaustive search.

-opt

cgo

Tells FRED] to optimize the candidate poses with CGO

-pose_select_weight_shapegauss

Sets the weight of Shapegauss to 0 in consensus structure.

-pose_select_weight_plp

Sets the weight of PLP to 0 in consensus structure.

-pose_select_weight_Chemgauss2

Sets the weight of Chemgauss3 to 0 in consensus structure.

-pose_select_weight_Chemgauss3

Sets the weight of Chemgauss3 to 0 in consensus structure.

-pose_select_weight_Chemscore

Sets the weight of Chemscore to 0 in consensus structure.

-pose_select_weight_oeChemscore

Sets the weight of OEChemscore to 0 in consensus structure.

-pose_select_weight_screenscore

Sets the weight of Screenscore to 0 in consensus structure.

-cgo

Tells FRED to score with CGO.

-cgt

Tells FRED to score with CGT.

6.6.2.4 Output

setup.txt: A file with the settings of all of FRED's parameters. Note that there will be many more parameters in this file than those specified on the command line because many parameters have default values. This file will be written at the beginning of the run.
receptor.oeb.gz: This file contains a copy of the receptor site used for the run. This file will be written at the beginning of the run.
status.txt: This file will be written every few seconds by FRED and indicates the status of the run.
cgo_docked.oeb.gz: contains the structure of the top 1000 docked ligands as ranked by CGO.
cgo_scores.txt: list the names, scores and SMILES representation of the top 1000 docked ligands as ranked by CGO in a text format.

				FRED Fast Rigid Exhaustive Docking

				FRED Fast Rigid Exhaustive Docking