Three pharmacophores

Fig. 12.27 The generation of 3-centre pharmacophore keys, illustrated using benperidol. Two different conformations are shown, together with two different combinations of three pharmacophore points.

It is common practice to enlarge the largest common denominator pharmacophore to include features which provide great potency but are not present in all active molecules. This is misleading. Examination of the published literature shows that molecules with only two of three pharmacophoric features can cause significant hERG block. 

Fig. 4.5 Examples of different scaffolds for ACE inhibitors having three pharmacophoric features separated by variable linker regions.

Fig. 8 Overlap of the three pharmacophores representing the interactions found for paclitaxel in the 1JFF structure (A), epothilone A in the NMR-derived structure (B), and epothilone A in the QSAR model from Botta and co-workers (C), respectively. Blue C7-OH (epothilones) oxetane ring (paclitaxel) red C13 carbon (epothilones) phenyl ring (paclitaxel) yellow Cl carbonyl oxygen (epothilones) Cl carbonyl oxygen (paclitaxel) purple thiazole ring (epothilone) C3 benzamide (paclitaxel). (3-tubulin monomer is represented as a green cartoon and residues involved in hydrogen bonds are in orange (hydrogens are omitted for sake of clarity)...

These three pharmacophoric elements are shown as emboldened atoms within the generalized beta-blocker structure 60. The key atoms in 60 should be considered to be discretely displayed in three-dimensional (3D) space via the oxypropyl-connecting chain, so as to be able to dynamically occupy a specified residence within the beta-receptor pocket, rather than to be merely residing in a static manner on the rigid plane that becomes defined by three points. For example, reconsidering the previously noted historical development wherein a surprising enhance-... 

PDT fingerprints (or Pharmacophore Definition Triplets fingerprints) are 3-point pharmacophore vectorial descriptors, where each bit is set to one or zero, depending on the presence or absence of a specific combination of three pharmacophoric points and three geometric distances [Matter and Potter, 1999]. 

Figure 15.1 CRID-based pharmacophore model of PRMTl inhibitors targeting the substrate binding site. The three pharmacophoric features are shown as colored spheres (positive ionizable blue, hydrophobic ...

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