Site-based pharmacophores

In addition, researchers can survey the surface and clefts of a macromolecule for potential receptor sites based on Hgand distance ranges "use the common distance range of the superimposed atoms" (116) to faciHtate the development of a "pharmacophore" or critical contact assembly besides the Hgand... 

Figure 6. An example of a relative pharmacophore given in the context of structure(site)-based design.

The concept of pharmacophore identification based on molecular electrostatic potentials has been reviewed [908]. Some other approaches to correlate biological activities with the interactions at certain positions of the binding site were discussed in chapter 2 (eqs. 17 and 18). 

Fig. 6.5 Proliferator-activated receptor (PPARy) partial agonist pharmacophore. Structure-based common pharmacophore derived ifom the alignment of PPARy partial agonists. The pharmacophore is formed by one hydrogen bond acceptor (API) coloured in pink and three hydrophobic sites (HPl, HPl saaAHPS) coloured in gKen. The ligand amorfrutin B (fiom the protein data bank (PDB) entry 4A4W) is also represented as a spatial reference. The pharmacophore was generated by Phase (Schrodinger)...

Based on the analysis of the DPP-IV ciystal stmctures [90-%] and the interpretation of the stracmre-activity relationship data, both the lipophiUc S, pocket and the Glu205/Glu206 (fyad can be considered as cmcial molecular anchors for DPP-IV inhibition [78], Moreover, this conclusion is supported by results derived from two different energetic pharmacophores [97,98] obtained by our group that have quantified the relative contribution of the different pharmacophore sites to the intermo-lecular interactions with DPP-IV. The first energetic pharmacophore was built from the PDB stracture of ten complexes of DPP-IV with potent (ICj values < 10 nM) reversible inhibitors of a nonpeptide nature (Fig. 7.3a) [99]. This study showed that... 

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