‘privileged structures’, which offer the basic scaffold and the substituents at different positions impart receptor specificity. Dihydropyridines [53],
Arylethylamines, N-arylpiperazines, diphenylmethane derivatives, biphenyls and
pyridazines [52, 53], tricyclic psychotropics and sulphonamides, benzodiazepines
[54] are among some popular examples of the privileged structures. Woods and
Fildes [55] found that p-aminobenzoic acid (PABA) and p-aminobenzenesulphonamide have similar critical distances; hence, bind to the PABA target with similar
efficacy and inhibits the biosynthesis of tetrahydrofolic acid. This was one of the
examples of the early two-dimensional pharmacophore models. An early 3D
pharmacophoric approach was the ‘three-point contact model’ proposed by Easson
and Stedman [56] and Beckett [48] in the case of (R)-(−)-adrenaline [= (R)-(−)epinephrine]. These models are based on a concept that when a chiral centre is
present in a compound, the substituents on this asymmetric atom make three-point
contacts with the binding pocket of the receptor, which can only be obtained for one
of the two isomers of epinephrine (the more active natural (R)-(−)-epinephrine).
Similarly, another three-dimensional approach was developed in the early 1970s,
characterizing the activity of clonidine on the central norepinephrine receptor [57].
It was observed that the natural ligand norepinephrine fits into the binding pocket of
its target by three main interactions [57], viz. ionic bond between an anion (carboxylate, phosphate) of the binding pocket and the protonated –NH 2 functional
group, a HB between the NH–CO group of the binding site and the secondary
alcoholic hydroxyl and a p-stacking between the protonated imidazole of a histidine
residue of the binding pocket and the aromatic ring of the drug. It was also recognized that the cationic head must be light and the phenolic –OH groups are not
important for the biological activity. Pullmann et al. [58] in their 3D pharmacophore model of the norepinephrine receptor computed the critical intramolecular
distances for the above key interactions which could successfully explain the
pharmacophoric similarity between clonidine and norepinephrine, which in
turn enables clonidine to make the same kind of interactions as norepinephrine.
Fig. 2 Schematic presentation of timeline showing early developments in the field of
pharmacophore modelling
Pharmacophore Modelling and Screening: Concepts, Recent …
31
Arylethylamines, N-arylpiperazines, diphenylmethane derivatives, biphenyls and
pyridazines [52, 53], tricyclic psychotropics and sulphonamides, benzodiazepines
[54] are among some popular examples of the privileged structures. Woods and
Fildes [55] found that p-aminobenzoic acid (PABA) and p-aminobenzenesulphonamide have similar critical distances; hence, bind to the PABA target with similar
efficacy and inhibits the biosynthesis of tetrahydrofolic acid. This was one of the
examples of the early two-dimensional pharmacophore models. An early 3D
pharmacophoric approach was the ‘three-point contact model’ proposed by Easson
and Stedman [56] and Beckett [48] in the case of (R)-(−)-adrenaline [= (R)-(−)epinephrine]. These models are based on a concept that when a chiral centre is
present in a compound, the substituents on this asymmetric atom make three-point
contacts with the binding pocket of the receptor, which can only be obtained for one
of the two isomers of epinephrine (the more active natural (R)-(−)-epinephrine).
Similarly, another three-dimensional approach was developed in the early 1970s,
characterizing the activity of clonidine on the central norepinephrine receptor [57].
It was observed that the natural ligand norepinephrine fits into the binding pocket of
its target by three main interactions [57], viz. ionic bond between an anion (carboxylate, phosphate) of the binding pocket and the protonated –NH 2 functional
group, a HB between the NH–CO group of the binding site and the secondary
alcoholic hydroxyl and a p-stacking between the protonated imidazole of a histidine
residue of the binding pocket and the aromatic ring of the drug. It was also recognized that the cationic head must be light and the phenolic –OH groups are not
important for the biological activity. Pullmann et al. [58] in their 3D pharmacophore model of the norepinephrine receptor computed the critical intramolecular
distances for the above key interactions which could successfully explain the
pharmacophoric similarity between clonidine and norepinephrine, which in
turn enables clonidine to make the same kind of interactions as norepinephrine.
Fig. 2 Schematic presentation of timeline showing early developments in the field of
pharmacophore modelling
Pharmacophore Modelling and Screening: Concepts, Recent …
31