Patterns Pharmacophore

Activity versus Affinity. Given a consistent model of either type, a limitation is that one can only ask whether the compound under consideration can present the three-dimensional electronic pattern (pharmacophore) that is the current candidate. In other words, one is limited to predicting the presence or absence of activity, a binary choice. Even the presence of the appropriate pattern is insufficient to ensure biological activity. For example, competition with the receptor for occupied space by other parts of the molecule can inhibit binding and preclude activity. We can thus postulate the following conditions for activity ... 

Gund P. Three-dimensional pharmacophoric pattern searching. Prog Mol Subcell Biol 1977 5 117-43. 

Jakes SE, Willett P. Pharmacophoric pattern matching in files of 3-D chemical structures selection of inter-atomic distance screens. / Mol Graph 1986 4 12-20. 

Clark DE, Willett P, Kenny PW. Pharmacophoric pattern matching in files of three-dimensional chemical structures use of smoothed bounded-distance matrices for the representation and searching of conformationally-fiexible molecules. J Mol Graph 1992 10 194-204. 

Gund P. Three-dimensional pharmacophore pattern searching. In Hahn FE, editor, Progress in molecular and subcellular biology. Berlin Springer-Verlag, 1977. p.117-43. 

The use of the phenyl phosphate group as both a solid support attachment site and a crucial binding element represents what has been referred to as a pharmacophore-linking strategy [26]. We explored a variety of phenyl phosphate tether functionalities to provide resins varying in substitution pattern and in chemical flexibility (Scheme 1 and Table 4) [22]. All phenyl phosphate resins were synthesized in batch quantities of 20 g or more. Resin synthesis began with the addition of either /mnethoxy-benzyl alcohol or benzyl alcohol to commercially available bis(diisopro-pylamino)chlorophosphine, followed by addition of the diversity phenol [(Ri)-OFl, DIAT (diisopropylamino tetrazole)]. Displacement of the... 

The Novartis group used the X-ray structure of a Grb2-peptide complex [68] as the structural basis for a design attempt that yielded entirely new non-peptide SH2 domain ligands [164]. As mentioned several times throughout this contribution, the interaction of the pTyr sidechain and the Asn sidechain in pTyr+2 position of the peptide ligand have been identified as key elements for molecular recognition (see Fig. 10). The obvious relevance of these two sidechain functionalities allowed the definition of a minimal pharmacophore pattern that... 

A pharmacophore model for FXR agonists based on 14 bile acid derivatives was reported by Ekins et al. The hypothesis consisted of three H features and one H BA - a common functionality pattern among steroidal compounds [42],... 

Figure 16.4 General pharmacophoric pattern of drugs at the verapamil-binding site of P-gp.

Gund, P., Wipke, W.T., Iangridge, R. Computer searching of a molecular structure file for pharmacophoric patterns. Comput. Chem. Res. Educ. Technol. 1974, 3, 5-21. 

ComPharm explicitly monitors pharmacophore patterns in calculating the intensities of six empirical pharmacophore fields described by Gaussian functions of the distance to their sources, which are the functional groups of the corresponding pharmacophore type. 

As a tool that delimits, out of the entire structural space, the zones most likely to harbor a higher density in active compounds ( Activity Zones ), all based on variations around a common pharmacophore pattern. 

As a tool that discriminates between the actives and inactives within the Activity zones, for example, to predict which of the local pharmacophore pattern variations will enhance and which will decrease activity. 

However, hypothesis models did clearly outperform similarity-based scoring with respect to the entire set. This advantage does not, as previously shown, stem from a better prediction of the subtle differences between the actives and inactives within the pharmacophoric Activity Zone . It may be ascribed to the ability of hypothesis models to correctly recognize actives that hide the key elements asked for by the model within a globally different pharmacophore pattern, which prevents them from being top ranked by the similarity search. 

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