Pharmacophoric restraints

In this short tutorial you will find how to prepare and run Docking with pharmacophoric restraints.

Note

rDock assumes the user knows how to compute and find pharmacophores. The user will need the coordinates, tolerance and type of restraint, which will be the input for rDock.

Step 1: Pharmacophoric restraints file

The first step is to create the input file for rDock with the necessary info.

As you can find in the User Manual, this file needs one line per pharmacophore withthe next structure (each element separated with a space):

x y z (coords of restraint centre), tolerance radius (in Angstroms), restraint type (string)

The pharmacophore types accepted by rDock are the following:

String

Description

Matches

Any

Any atom

Any non-hydrogen atom

Don

H-Bond donor

Any neutral donor hydrogen

Acc

H-Bond acceptor

Any neutral acceptor

Aro

Aromatic

Any aromatic ring centre (pseudo atom)

Hyd

Hydrophobic

Any C or S sp3, any C od S not bonded to O sp2, any Cl, Br, I

Hal

Hydrophobic, aliphatic

Subset of Hyd, sp3 atoms only

Har

Hydrophobic, aromatic

Subset of Hyd, aromatic atoms only

Ani

Anionic

Any atom with negative distributed formal charge

Cat

Cationic

Any atom with positive distributed formal charge

A sample file (pharma.restr) has been created containing two restraints (Acc and ``Hyd) with a tolerance radius of 2 and located at points (-1.75,1.25,0.25) and (-2,2,-3) respectively.

-1.75 1.25 0.25 2.0 Acc
-2.00 2.00 -3.0 2.0 Hyd

Step 2: rDock system definition file

The second and final step is to modify the system definition file (FILE.prm) to take into account the defined restraints.

Just add a SECTION PHARMA (see the User Guide for more info) with the following lines:

SECTION PHARMA
    SCORING_FUNCTION RbtPharmaSF
    WEIGHT 1.0
    CONSTRAINTS_FILE pharma.restr
END_SECTION

With the FILE.prm finally being:

RBT_PARAMETER_FILE_V1.00
TITLE title

RECEPTOR_FILE receptor_file.mol2
RECEPTOR_FLEX 3.0

##############################################
## CAVITY DEFINITION: REFERENCE LIGAND METHOD
##############################################
SECTION MAPPER
    SITE_MAPPER RbtLigandSiteMapper
    REF_MOL reference.sdf
    RADIUS 5.0
    SMALL_SPHERE 1.0
    MIN_VOLUME 100
    MAX_CAVITIES 1
    VOL_INCR 0.0
    GRIDSTEP 0.5
END_SECTION

############################
## CAVITY RESTRAINT PENALTY
############################
SECTION CAVITY
    SCORING_FUNCTION RbtCavityGridSF
    WEIGHT 1.0
END_SECTION

#############################
## PHARMACOPHORIC RESTRAINTS
#############################
SECTION PHARMA
    SCORING_FUNCTION RbtPharmaSF
    WEIGHT formal charge
    CONSTRAformal charge
END_SECTIONformal charge

Note

This FILE.prm is an example file for the sake of the tutorial. The point here is to clarify how to define pharmacophoric restraints and how to configure rDock to take them into account.

Finally, when running rDock, the user can check if the program writes similar lines as the following to be sure that the restraints have been correctly read.

[...]
RbtPharmaSF: Reading mandatory ph4 constraints from /path/to/pharma.restr
(-1.75,1.25,0.25)  2.0     Acc
(-2.0,2.0,-3.0)    2.0     Hyd
RbtPharmaSF: No optional ph4 constraints file found
[...]

Step 3: Optional constraints

This tutorial is an example for mandatory constraints. Optional constraints can also be configured in a different file (same format as pharma.restr created above). The “SECTION PHARMA” in the rDock System Configuration File should be modified as follows (NOPT=1 means that only one of the optional restraints has to be met):

SECTION PHARMA
    SCORING_FUNCTION RbtPharmaSF
    WEIGHT 1.0
    CONSTRAINTS_FILE pharma.restr
    OPTIONAL_FILE optional_pharma.restr
    NOPT 1
END_SECTION

For more information about the pharmacophoric restraints and the parameters in SECTION PHARMA, please go to the User Guide.