Along with defining the HB features, it is very essential to fix the positions of the
complementary feature points to be overlapped in the resulting pharmacophore.
That is why the pharmacophore modelling programmes link donor and acceptor
features with the equivalent ligand atoms as well as the supposed locations of the
corresponding complementary receptor atoms involved in the interaction.
Positive and negative features (P and N): In the molecules, atoms bearing formal
charges are considered as positive or negative features provided they are not part of
a dipole. Groups possessing net formal charges are also considered as positive/
negative features. Centroid of the heteroatoms of a group is the region, where the
positive/negative charged features are generally placed. Sometimes the positive and
negative features are emphasized specifically based on their ionizability. For
example, R–NH 3
+ is measured as positively ionizable feature, but R–N(Me) 3
+ is not
as the interactions made by these two groups are significantly different.
Hydrophobic features (H): Choosing atoms/groups that should be measured as
hydrophobic is neither easy nor straightforward. The most commonly used algorithm developed by Greene et al. [42] first allot a hydrophobicity score to each atom
based on a set of empirical rules defined from medicinal chemists’ perceptions and
then atoms with amply large hydrophobicity values are grouped into clusters. Then
a hydrophobic feature point is placed at the centroid of each such cluster. The order
of hydrophobicity score is roughly rings/ring atoms > groups like –CF 3 > alkyl
chains. Some simple algorithms [44] consider all non-donors/non-acceptor/
non-charged atoms as steric groups (equivalent of hydrophobic groups), which
also yield a depiction of molecular shape.
Aromatic rings (R): Aromatic rings are treated as a special type of hydrophobic
feature represented by vectors instead of points so as to mimic the directionality of
interactions like p–p stacking and cation–p interactions. Figure 1 shows an
example of a typical pharmacophore model.
Fig. 1 An example of a pharmacophore model, generated from the conformations of S-adenosyl
methionine (SAM) and S-adenosyl homocysteine (SAHC) [17] with Phase programme. Colour
codes for the pharmacophoric features are as follows. Cyan: D, pink: A, red: N, blue: P, green: H
and orange: R
Pharmacophore Modelling and Screening: Concepts, Recent …
29
complementary feature points to be overlapped in the resulting pharmacophore.
That is why the pharmacophore modelling programmes link donor and acceptor
features with the equivalent ligand atoms as well as the supposed locations of the
corresponding complementary receptor atoms involved in the interaction.
Positive and negative features (P and N): In the molecules, atoms bearing formal
charges are considered as positive or negative features provided they are not part of
a dipole. Groups possessing net formal charges are also considered as positive/
negative features. Centroid of the heteroatoms of a group is the region, where the
positive/negative charged features are generally placed. Sometimes the positive and
negative features are emphasized specifically based on their ionizability. For
example, R–NH 3
+ is measured as positively ionizable feature, but R–N(Me) 3
+ is not
as the interactions made by these two groups are significantly different.
Hydrophobic features (H): Choosing atoms/groups that should be measured as
hydrophobic is neither easy nor straightforward. The most commonly used algorithm developed by Greene et al. [42] first allot a hydrophobicity score to each atom
based on a set of empirical rules defined from medicinal chemists’ perceptions and
then atoms with amply large hydrophobicity values are grouped into clusters. Then
a hydrophobic feature point is placed at the centroid of each such cluster. The order
of hydrophobicity score is roughly rings/ring atoms > groups like –CF 3 > alkyl
chains. Some simple algorithms [44] consider all non-donors/non-acceptor/
non-charged atoms as steric groups (equivalent of hydrophobic groups), which
also yield a depiction of molecular shape.
Aromatic rings (R): Aromatic rings are treated as a special type of hydrophobic
feature represented by vectors instead of points so as to mimic the directionality of
interactions like p–p stacking and cation–p interactions. Figure 1 shows an
example of a typical pharmacophore model.
Fig. 1 An example of a pharmacophore model, generated from the conformations of S-adenosyl
methionine (SAM) and S-adenosyl homocysteine (SAHC) [17] with Phase programme. Colour
codes for the pharmacophoric features are as follows. Cyan: D, pink: A, red: N, blue: P, green: H
and orange: R
Pharmacophore Modelling and Screening: Concepts, Recent …
29