Pharmacophoric restraints

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

Note

RxDock 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 RxDock.

Step 1: Pharmacophoric restraints file

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

As you can find in the Reference guide, this file needs one line per pharmacophore with the 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 RxDock 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: RxDock 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 Reference 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 1.0
    CONSTRAINTS_FILE pharma.restr
END_SECTION

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 RxDock to take them into account.

Finally, when running RxDock, 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 RxDock 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

Tip

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