Pharmacophore Models into Receptor Site

Mapping of Pharmacophore Models into Receptor Site 

Numerous site-directed mutagenesis studies have provided a conclusive picture for the molecular interactions between the receptor-activating biogenic amines (e.g. serotonin, epinephrine, dopamine) and their receptors [23-27] a highly conserved aspartate residue in transmembrane (TM) helix TM3 (Asp 3.32 according to the Ballosteros-Weinstein nomenclature) [28], conserved serine residues in TM5 (e.g. 

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Mapping of Pharmacophore Models into Receptor Site 292... 

Figure 13.5 Topographical interaction model of ana adrenergic receptor generated based on public site-directed mutagenesis. Both pharmacophore models have been mapped into the topographical model of the receptor. The model reveals putative receptor interaction sites for most of the pharmacophoric features observed within each antagonist class, (a) Class I pharmacophore with prazosin as reference compound (b) class II pharmacophore with compound 10 as reference. Pharmacophoric features are red for posi-...

How is the target represented Most methods require the existence of a high resolution experimental three-dimensional structure or a homology model of the receptor active site into which ligands are fitted. Other methods, however, will work with just a pharmacophore model or with some kind of molecular field or pseudopotential model. 

If only the structure of the enzyme/receptor is known, energy calculations between functional group probes and the active site residues of the enzyme/ receptor can be used to determine favourable positions ( hot spots ) to place the functional group. These hot spots can readily be converted into a pharmacophore model for use in a 3-D search. 

The spatial, elearonic, and lipophilic features of a molecule that allow recognition and binding at a receptor constitute a pharmacophore. Information on the pharmacophore can be used to design compounds which, although they may be structurally very dissimilar from the compounds used to create the model, are predicted to fit into the active site. This is especially important in the pharmaceutical industry where nonobviousness is a requirement for patentability. 

The next step is to translate this interaction field into a model of the receptor which is composed from single isolated amino acids with chemical properties that satisfy the different types of binding present in the pharmacophore. The relative three-dimensional positions of the amino acid binding sites are defined by the corresponding GRIN/GRID results. The resulting amino acid receptor model is sometimes called a pseudoreceptor. ... 

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