1. Standard Pharmacophore Features

How to define an AnchorQuery pharmacophore.

1. Standard Pharmacophore Features

Postby dkoes » Wed Jan 12, 2011 1:08 pm

pharmas.png
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Example standard 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, match, enabled, and required properties. Some feature types also have feature-specific constraints, such as direction vectors.

Editing Standard Features
editstandardsm.png
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Pharmacophore query editor

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, require/unrequire, 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)
arom.png
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Parallel orientation

tarom.png
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T-Shaped orientation

SMARTS:
Code: Select all
a1aaaaa1
a1aaaa1

Aromatic features have an additional directionality constraint that is specified using spherical coordinates and an orientation. The orientation can either be parallel (i.e., ring stacking) or the less common T-shaped. The constraint will match features that deviate from the desired orientation by as much as 45 degrees.

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. The tolerance can be narrow (~45 degree deviation from ideal allowed), wide (~90 degree deviation), or non-existent (any direction allowed). 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 and so a wider tolerance is generally desired.

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.

Heavy Atom (grey)
SMARTS
Code: Select all
[!#1]

This feature matches the center of any heavy atom in a compound. It can be further constrainted by specifying a range of atomic numbers.

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.

Match
A value attributed to each feature that is summed to create a Match score of a hit compound. This can be used to partially implement some boolean expressions and screen out undesirable features. For example, if you want to match at least one of three hydrogen bond features, you can make all three optional, but specify a minimum match filter so that at least one feature is matched in every compound in the hit list.

This value can be negative. If a feature is required and has a negative match, only compounds not containing that feature at that location are returned.

Required
If selected, compound must contain the feature to be a hit. There must be at least one required feature. Optional features are considered to match of the compound has the corresponding feature when optimally aligned to the required features.

Enabled
A disabled feature is not part of the query, but remains in the editor for future reference.
dkoes
 
Posts: 67
Joined: Mon Nov 15, 2010 9:05 am

Re: 1. Standard Pharmacophore Features

Postby luterngreen » Wed May 23, 2012 1:06 am

Hello
I'm quite intrigued. Can I create a custom feature using smarts ?
Thanks
luterngreen
 
Posts: 1
Joined: Wed May 23, 2012 12:55 am

Re: 1. Standard Pharmacophore Features

Postby dkoes » Wed May 23, 2012 6:02 am

Nope, custom features are not supported. You can make suggestions for improvements though.
dkoes
 
Posts: 67
Joined: Mon Nov 15, 2010 9:05 am


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