Receptor mapping pharmacophores

The essential feature of the AAA is a comparison of active and inactive molecules. A commonly accepted hypothesis to explain the lack of activity of inactive molecules that possess the pharmacophoric conformation is that their molecular volume, when presenting the pharmacophore, exceeds the receptor excluded volume. This additional volume apparently is filled by the receptor and is unavailable for ligand binding this volume is termed the receptor essential volume [3]. Following this approach, the density maps for each of the inactive compounds (in their pharm conformations superimposed with that of active compounds) were constructed the difference between the combined inactive compound density maps and the receptor excluded volume represents the receptor essential volume. These receptor-mapping techniques supplied detailed topographical data that allowed a steric model of the D[ receptor site to be proposed. 

DM Mottola, S Laiter, VJ Watts, A Tropsha, SW Wyrick, DE Nichols, P Mailman. Conformational analysis of d dopamine receptor agonists Pharmacophore assessment and receptor mapping. J Med Chem 39 285-296, 1996. 

Chapter 29. Pharmacophoric Pattern Searching and Receptor Mapping Peter Gund, Merck Sharp Dohiae Research Laboratories, Rahway, NJ 07065... 

Pharmacophoric patterns have been proposed as the result of structure-activity studies, modeling studies, mechanistic studies, and enzyme structural studies. While two atom ("distance") and three atom ("triangle") pharmacophoric patterns have been proposed, we would not expect these to be as discriminating as more detailed patterns. Proposed pharmacophoric patterns have been reviewed by Kler,9 Korolkovas,10 and Gund.7 Some additional proposed patterns of drug pharmacophores and of complementary receptor maps are listed in Table I. 

Pharmacophoric Patter Searching in Receptor Mapping Peter Gund ii. ... 

To discover novel non-indole classes of glycine antagonists as potential back-up to GV150526A, new templates were designed by receptor mapping techniques based on the pharmacophore model of the glycine binding site (Di... 

The synthesis and subsequent confirmation of the predicted structures by pharmacological testing is the final and decisive proof for the correctness or, more precisely, the usefulness of the deduced receptor map of the pharmacophore. The derived pharmacophore model then allows conclusions regarding the structure and properties of the unknown receptor binding site. 

To portray the routes to be followed for pharmacophore identification and receptor mapping in practice, the complete suite of procedures will be demonstrated using an example from the author s laboratory. 

The example reported demonstrates that theoretical methods such as pharmacophore identification and receptor mapping can be successfully employed as predictive tools in medicinal chemistry. 

The parameter (c) above aids in determining the precise location of the available receptor-occupied space with respect to the particular pharmacophore (i.e., actual receptor mapping). ... 

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