Pharmacophoric groups, definition

The structure-based pharmacophore was built using the crystallographic coordinates of argatroban complexed with thrombin [101] and the functional group definitions contained within the CATALYST software to predict the effects on the K[ values of structural modification of a set of homologous 4-aminopyridine (4-AP) thrombin inhibitors. 

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... 

Since the appearance of computer-aided structure-activity studies, the term pharmacophore has become one of the most popular words in medicinal chemistry. However, depending on their scientific background and/or traditions, the different medicinal chemistry groups attribute various meanings to this term. Therefore, it appeared necessary to devote a brief paragraph to the definition of the word pharmacophore, and this is followed by a historical perspective and finally by some comments from a medicinal chemistry practitioner. 

According to these definitions, each atom of a molecule is assigned to no, one or two PPPs. Since the descriptor is based on atom pairs, a pharmacophore matrix is built up. The entries py of the pharmacophore matrix P hold the PPP pair of vertex i and vertex j. If an atom is not a member of any PPP group, the row and column that correspond to the atom remain empty. A single atom can also belong to more than one PPP group. In this case, the entry py of the pharmacophore matrix P holds more than one PPP pair. All possible pairing combinations of the five PPPs result in 15 pairs (DD, DA, DP, DN, DL, AA, AP, AN, AL, PP, PN, PL, NN, NL, LL). 

Classification according to a substituent is of course unusual, since medicinal chemists conventionally group structures by their common core, thought to define a pharmacophoric element, and a set of substituents which, by definition, do not... 

A pharmacophore does not represent a real molecule or a real association of functional groups but is a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds toward their target structure. The pharmacophore can be considered to be the largest common denominator shared by a set of active molecules. This definition discards a misuse often found in the MEDICINAL CHEMISTRY literature, which consists of naming as pharmacophores simple chemical functionalities such as guanidines, sulfonamides, or dihydroimidazoles (formerly imidazolines), or typical structural skeletons such as flavones, phenothiazines, prostaglandins, or steroids. 

The term pharmacophore is used by different group of scientists not always in accordance with the official definition elaborated by the lUPAC working party which... 

The imphcation within this definition is that compounds, which share a pharmacophoric pattern pertinent to a particular target, are likely to bind to the said target. There are several important caveats to this statement that should be kept in mind. First, as defined, a pharmacophore is necessary but not sufficient for activity. The binding energy will be determined by other properties of the molecule not imphed by the pharmacophore, e.g., additional groups could lead to a steric clash with the... 

Tab. 4.1 Examples of commonly defined functional group equivalences and the corresponding pharmacophoric definition.

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