present in the target’s binding pocket. The general features include hydrogen-bond
(HB) donors, HB acceptors, charged groups (positive and negative), hydrophobic
sites and aromatic rings, which are used as chemical features in pharmacophore
models by most of the programmes. Some programmes define a few additional
features such as ‘exclusion volumes’ representing steric constraints. These features
generally replicate the steric environment of the binding pocket to avoid clashes of
the mapped of compounds with the protein surface. Pharmacophore models comprises distinct spatial arrangement of these features that denotes the chemical
functionalities of active small molecules. Instead of real atoms/functional groups, a
pharmacophore model emphasizes the chemical features of ligands/protein–ligand
complexes, making it a better and fast tool to recognize molecular similarities.
3 A Typical Pharmacophore Model: Representation
of Pharmacophoric Features
According to the definition, a pharmacophore model represents the binding patterns
of bioactive molecules with the target binding site, by virtue of a distinct 3D
arrangement of abstract interaction features accounting for different types of
non-covalent interactions. These interaction types can be HB formation, columbic
interactions, metal interactions, hydrophobic contacts, aromatic stacking or charge
transfer interactions. Overall, a pharmacophore model characterizes a common
binding mode of diverse ligands with a specific target. In pharmacophore modelling, the molecules are first segregated into a set of features, each representing a
certain type of interaction with the binding site residues. Then, each feature is
represented by points to be used for superimposition (least-squares fitting) of
molecules with each other. Here we will be discussing features employed by most
of the popular programmes [41–45].
HB donor (D): Hydroxyl groups, hydrogens bound to nitrogen, acetylenic CH
groups and thiols (SH) are normally denoted as donors. However, the –CH and –SH
groups are considered relatively weaker donors. Sometimes, along with acetylenes,
other types of –CH such as the ones in nitrogen heterocycles of some kinase
inhibitors are considered as donors. Keeping protonation in mind, basic amines
such as RCH 2 N(Me) 2 are considered as donors. Tautomeric and ionized states
severely influence pharmacophore feature definition because they may amend the
characteristic of a feature. Hence, molecules should be presented to the pharmacophore elucidation programmes in all possible protonation/ionization states.
HB acceptor (A): Generally, atoms with available lone pairs of electrons such as
N, O, S are treated as acceptors. However, some programmes do not consider
oxygen atoms present in furan/oxazole rings, as they are very weak acceptors
according to theoretical and crystallographic evidence.
28
C. Choudhury and G. Narahari Sastry
(HB) donors, HB acceptors, charged groups (positive and negative), hydrophobic
sites and aromatic rings, which are used as chemical features in pharmacophore
models by most of the programmes. Some programmes define a few additional
features such as ‘exclusion volumes’ representing steric constraints. These features
generally replicate the steric environment of the binding pocket to avoid clashes of
the mapped of compounds with the protein surface. Pharmacophore models comprises distinct spatial arrangement of these features that denotes the chemical
functionalities of active small molecules. Instead of real atoms/functional groups, a
pharmacophore model emphasizes the chemical features of ligands/protein–ligand
complexes, making it a better and fast tool to recognize molecular similarities.
3 A Typical Pharmacophore Model: Representation
of Pharmacophoric Features
According to the definition, a pharmacophore model represents the binding patterns
of bioactive molecules with the target binding site, by virtue of a distinct 3D
arrangement of abstract interaction features accounting for different types of
non-covalent interactions. These interaction types can be HB formation, columbic
interactions, metal interactions, hydrophobic contacts, aromatic stacking or charge
transfer interactions. Overall, a pharmacophore model characterizes a common
binding mode of diverse ligands with a specific target. In pharmacophore modelling, the molecules are first segregated into a set of features, each representing a
certain type of interaction with the binding site residues. Then, each feature is
represented by points to be used for superimposition (least-squares fitting) of
molecules with each other. Here we will be discussing features employed by most
of the popular programmes [41–45].
HB donor (D): Hydroxyl groups, hydrogens bound to nitrogen, acetylenic CH
groups and thiols (SH) are normally denoted as donors. However, the –CH and –SH
groups are considered relatively weaker donors. Sometimes, along with acetylenes,
other types of –CH such as the ones in nitrogen heterocycles of some kinase
inhibitors are considered as donors. Keeping protonation in mind, basic amines
such as RCH 2 N(Me) 2 are considered as donors. Tautomeric and ionized states
severely influence pharmacophore feature definition because they may amend the
characteristic of a feature. Hence, molecules should be presented to the pharmacophore elucidation programmes in all possible protonation/ionization states.
HB acceptor (A): Generally, atoms with available lone pairs of electrons such as
N, O, S are treated as acceptors. However, some programmes do not consider
oxygen atoms present in furan/oxazole rings, as they are very weak acceptors
according to theoretical and crystallographic evidence.
28
C. Choudhury and G. Narahari Sastry