Pharmacophore Definition

Getting the most out of ZINCPharmer

Pharmacophore Definition

Postby dkoes » May 27th, 2011, 1:56 pm

A pharmacophore is a collection of essential structural features of an interaction. ZINCPharmer supports the standard hydrophobic (green), hydrogen bond donor (white), hydrogen bond acceptor (orange), positive ion (blue), negative ion (red), and aromatic (purple) features.

Standard features are identified using SMARTS expressions. A compound matches a standard feature if the feature location falls within the tolerance sphere in the optimal RMSD alignment. Standard features all have location, radius, and enabled properties. Some feature types also have feature-specific constraints, such as direction vectors.

Note: Direction vectors are currently only approximately matched with no option to specify the amount of angular tolerance.

Creating a Pharmacophore
Ligand Based

Use the Load Features... button to upload a ligand structure. All major molecular formats are supported (specifically, any format supported by OpenBabel). If you encounter an error uploading what you believe to be a valid structure file, try converting it with babel to see if an error is reported (OpenBabel can be finicky, especially with regards to PDB files). ZINCPharmer will automatically use its built-in SMARTS rules (see below) to populate the query editor with the potential pharmacophore features of the ligand.


Interaction Based

If a receptor has been loaded (using Load Receptor), then uploading a ligand will cause ZINCPharmer to identify only the most meaningful pharmacophore features of the interaction. Simple distance cut-offs between receptor features and the ligand features are used to select the interacting features. Specifically, any aromatic or ionic features of the ligand that are within 5 Angstroms of a complementary feature on the receptor are retained. For hydrogen bonds, the complementary feature must be within 4 Angstroms. Hydrophobic features must be within 6 Angstroms of at least three hydrophobic features of the receptor. Non-interacting features are retained, but marked as disabled.

Third Party Import

Pharmacophore definitions created by the commercial packages MOE (.ph4 format) or LigandScout (.pml format) can be uploaded as features. ZincPharmer will load the compatible features and ignore any incompatible features (such as volume exclusion spheres). Additionally, the specialized mol2 format exported by the freely available PharmaGist is correctly recognized as a combined pharmacophore definition and ligand structure file. Since PharmaGist does not provide suggested tolerances for the features, the default values are used instead and should probably be adjusted to better match the alignment.

Manual

Features can be manually added using the Add button or the Duplicate contextual menu option. For example, the Add button might be used to add a hydrogen bond feature extracted from a water molecule in the original crystal.

Editing Features

All feature properties can be interactively edited in the pharmacophore query editor. Features can be selected by clicking on the left-most column, which will highlight the feature in the molecular viewer. Shift-click can be used to select a range of features and Ctrl-click to select (or deselect) multiple individual features. Features can also be selected in the molecular viewer (these clicks are sticky).

Selected features can be batch edited by right clicking. The resulting contextual menu can be used to enable/disable, delete and duplicate selected features. Features can also be deleted using the delete key (do not use backspace - this is mapped to "go back" in many browsers).

The pharmacophore features can be sorted by any of the standard properties (this can be useful, for instance, if you want to partition the enabled and disabled features).

Pharmacophore Classes
Aromatic (purple)

SMARTS:
Code: Select all
a1aaaaa1
a1aaaa1

Aromatic features have an additional directionality constraint that is specified using spherical coordinates and an orientation.

Hydrogen Donor and Acceptor (white and orange)

Donor SMARTS:
Code: Select all
[#7!H0&!$(N-[SX4](=O)(=O)[CX4](F)(F)F)]
[#8!H0&!$([OH][C,S,P]=O)]
[#16!H0]


Acceptor SMARTS:
Code: Select all
[#7&!$([nX3])&!$([NX3]-*=[!#6])&!$([NX3]-[a])&!$([NX4])&!$(N=C([C,N])N)]
[$([O])&!$([OX2](C)C=O)&!$(*(~a)~a)]


Hydrogen bond features include a directionality constraint specified with spherical coordinates and a tolerance. Since hydrogen bond directions depend on the properties of both the ligand and the receptor, the precomputed directions of the library compounds should be assumed to be highly approximate.

Positive/Negative Ion (blue/red)
Positive SMARTS:
Code: Select all
[+,+2,+3,+4]
//amidine
[$(CC)](=N)N
//guanidine
[$(C(N)(N)=N)]
[$(n1cc[nH]c1)]

Negative SMARTS:
Code: Select all
[-,-2,-3,-4]
C(=O)[O-,OH,OX1]
[$([S,P](=O)[O-,OH,OX1])]
c1[nH1]nnn1
c1nn[nH1]n1
C(=O)N[OH1,O-,OX1]
C(=O)N[OH1,O-]
CO(=N[OH1,O-])
//trifluoromethyl sulfonamide
[$(N-[SX4](=O)(=O)[CX4](F)(F)F)]


Ionic features have no additional constraints.

Hydrophobic (green)
SMARTS:
Code: Select all
a1aaaaa1
a1aaaa1
//branched terminals as one point
[$([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])&!$(**[CH3X4,CH2X3,CH1X2,F,Cl,Br,I])]
[$(*([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])[CH3X4,CH2X3,CH1X2,F,Cl,Br,I])&!$(*([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])[CH3X4,CH2X3,CH1X2,F,Cl,Br,I])]([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])[CH3X4,CH2X3,CH1X2,F,Cl,Br,I]
*([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])([CH3X4,CH2X3,CH1X2,F,Cl,Br,I])[CH3X4,CH2X3,CH1X2,F,Cl,Br,I]
//simple rings only; need to cluster points to get good results for 3d structures
[C&r3]1~[C&r3]~[C&r3]1
[C&r4]1~[C&r4]~[C&r4]~[C&r4]1
[C&r5]1~[C&r5]~[C&r5]~[C&r5]~[C&r5]1
[C&r6]1~[C&r6]~[C&r6]~[C&r6]~[C&r6]~[C&r6]1
[C&r7]1~[C&r7]~[C&r7]~[C&r7]~[C&r7]~[C&r7]~[C&r7]1
[C&r8]1~[C&r8]~[C&r8]~[C&r8]~[C&r8]~[C&r8]~[C&r8]~[C&r8]1
//aliphatic chains
[CH2X4,CH1X3,CH0X2]~[CH3X4,CH2X3,CH1X2,F,Cl,Br,I]
[CH2X4,CH1X3,CH0X2]~[CH2X4,CH1X3,CH0X2]~[$([CH2X4,CH1X3,CH0X2]~[$([!#1]);!$([CH2X4,CH1X3,CH0X2])])]
[CH2X4,CH1X3,CH0X2]~[CH2X4,CH1X3,CH0X2]~[CH2X4,CH1X3,CH0X2]~[$([CH2X4,CH1X3,CH0X2]~[CH2X4,CH1X3,CH0X2]~[$([CH2X4,CH1X3,CH0X2]~[$([!#1]);!$([CH2X4,CH1X3,CH0X2])])])]
// sulfur
[$([S]~[#6])&!$(S~[!#6])]


Hydrophobic feature points are clustered at a radius of 2.0 Angstroms and only the center of the cluster is retained as a pharmacophore feature. This greatly simplifies the definition of complex, heterocyclic hydrophobic structures.
Hydrophobic features can be additionally constrained by the number of atoms defining the feature. For example, a methyl group is defined by one atom while a benzene ring is defined by six.

Standard Properties

Location
The location of a feature center is specified with standard x,y,z Cartesian coordinates with Angstrom units. These values can be interactively edited.

Radius
The radius of the tolerance sphere of each feature is specified in Angstroms and can be interactively edited.

Enabled
A disabled feature is not part of the query, but remains in the editor for future reference.
dkoes
Site Admin
 
Posts: 24
Joined: May 27th, 2011, 11:29 am

Re: Pharmacophore Definition

Postby DianaDrennan » April 13th, 2012, 4:24 pm

Hi,
I'm new to this site, and am intrigued. Can I create a custom feature using smarts ?
Thanks,
Di
DianaDrennan
 

Re: Pharmacophore Definition

Postby dkoes » April 13th, 2012, 4:32 pm

The features are defined at database creation time, so you cannot customize feature definitions within ZINCPharmer. However, if you use the underlying Pharmer software (pharmer.sf.net) to build a custom database on your own machine then you can customize the pharmacophore descriptions however you want.
dkoes
Site Admin
 
Posts: 24
Joined: May 27th, 2011, 11:29 am

Re: Pharmacophore Definition

Postby ahsanbd98 » September 8th, 2012, 3:19 am

I am new and i do the registration by answering the question only one time :) http://en.wikipedia.org/wiki/Pharmacophore
ahsanbd98
 

Re: Pharmacophore Definition

Postby colliandre » September 20th, 2012, 8:51 am

Hi Dkoes,

Please, can you explain how to create a database with new pharmacophores features with the Pharmer software?

Is-it with the "pharmaspec" option?

In fact I do not want to create new feature, but only to detect Hacceptor that are not detected for the moment.

For example: the O atom in the Ph-O-Ph scaffold or the S atom in thiophene rings.

Thanks for your help.

Lionel
colliandre
 
Posts: 2
Joined: September 20th, 2012, 8:45 am

Re: Pharmacophore Definition

Postby dkoes » September 20th, 2012, 11:47 am

Since this is unrelated to ZINCPharmer, I have answered your question in the Pharmer forum:
https://sourceforge.net/p/pharmer/discussion/1669176/thread/900f448c/

Please feel free to post the SMARTS expressions that you would like to add to the HydrogenAcceptor defintion and I will add them to the default set.

colliandre wrote:Hi Dkoes,

Please, can you explain how to create a database with new pharmacophores features with the Pharmer software?

Is-it with the "pharmaspec" option?

In fact I do not want to create new feature, but only to detect Hacceptor that are not detected for the moment.

For example: the O atom in the Ph-O-Ph scaffold or the S atom in thiophene rings.

Thanks for your help.

Lionel
dkoes
Site Admin
 
Posts: 24
Joined: May 27th, 2011, 11:29 am

Re: Pharmacophore Definition

Postby colliandre » September 21st, 2012, 6:53 am

dkoes wrote:Since this is unrelated to ZINCPharmer, I have answered your question in the Pharmer forum:
https://sourceforge.net/p/pharmer/discussion/1669176/thread/900f448c/

Please feel free to post the SMARTS expressions that you would like to add to the HydrogenAcceptor defintion and I will add them to the default set.


Thanks for your explanations. I will try it and say you if all is working (of cource on the Pharmer forum).
colliandre
 
Posts: 2
Joined: September 20th, 2012, 8:45 am


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