Pharmacophoric groups

The pharmacophore concept is based upon the premise that different chemical groups can have the same types of interaction with a protein. For example, carboxylic acids, certain sulfonamides, and tetrazoles are acidic and so can be made equivalent in a pharmacophore context. In order to achieve this equivalence, how- 

For a ligand donor atom such as a hydroxyl, fhe approximate position of the receptor acceptor atom is defined along fhe O-H bond vector. Account needs to be taken of possible rotation of fhe O-H group. Fig. 4.2 illustrates the principle of re- 

Having defined the appropriate pharmacophore features, the expert must next derive the pharmacophore of interest. A prerequisite, in the absence of a protein structure, is a series of active molecules that are presumed to bind in the same way. The pharmacophore may then be derived from examining the disposition of pharmacophore features within the molecules to locate common distances and then generating a superposition of the molecules. The key elements of this process are pharmacophore feature perception, described above, conformational analysis to explore the conformational space of the ligands, and identification of the common features. 

developed by Yvonne Martin s group at Abbott, and the HipHop [24] module of Catalyst, rely upon pre-calculated conformers. For DISCO these can be generated using a standard modeling package. The Catalyst suite includes a mod- 

All of the automated methods will return multiple solutions (pharmacophores). 

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There are two problems to consider when calculating 3D pharmacophores. First, unless the molecules are all completely rigid, one must take account of their conformational properties The second problem is to determine which combinations of pharmacophoric groups are common to the molecules and can be positioned in a similar orientation in space. More than one pharmacophore may be possible indeed, some algorithms can generate hundreds of possible pharmacophores, which must then be evaluated to determine which best fits the data. It is important to realise that all of these approaches to finding 3D pharmacophores assume that all of the molecules bind in a common manner to the macromolecule. 

A variant of distance geometry called ensemble distance geometry [Sheridan et al. 1986] can be used to simultaneously derive a set of conformations with a previously defined set of pharmacophoric groups overlaid. Ensemble distance geometry uses the same steps as... 

When many pharmacophoric groups are present in the molecule it may be very difficult to identify all possible combinations of the functional groups (there may be thousands of... 

Yet another example of a so-called pharmacophoric group is the biguanide functionality, a grouping associated with oral antidiabetic activity (see the section on sulfonylureas for a fuller discussion of this activity). Condensation of 2-phenethylamine with dicyanamide affords directly the orally active hypoglycemic agent phenformin (88). ... 

The requirement for diverse compound libraries by means of solid-phase synthesis led to the development of hnkers for most functional groups found in organic synthesis. The number of hnkers developed for a specific group also reflects the distribution of pharmacophoric groups present in natural products and other bioactive compounds. Tab. 3.16 gives an overview of examples of hnkers for different functional groups. 

Fig. 1.2 Schematic diagram of minimization approach to the overiap of pharmacophoric groups (A with A with A", B with B with B",...

Specifies rotatable bond atom types between components Specifies atom type requirements in a specific component Specifies bonded atom types within a specific component Specifies pharmacophoric group at coordinates xyz ... 

In this template, the lead compound fragment and the two pharmacophoric groups are separated by wildcard designations that denote where chemical variability can occur. 

Protriptyline Protriptyline, A-methyl-5-//-dibenzo[a,d]cyclohepten-5-propylamine (7.1.22), differs from all of the drugs described above in that there is present a double bond at the Cio-Cji position of the central 7-membered ring of the tricyclic part of the molecule. At the same time, a free electron pair on C, belonging to either a nitrogen atom or an exo-cyclic double bond are excluded, which undoubtedly changes both the architecture of the whole molecule as well as, the collocation of pharmacophore groups. 

As illustrated by the examples sketched in Fig. 5, pharmacophore-rich thiols and amines could be used in all three displacement reactions to yield substituted benzamides displaying highly variable arrangements of different pharmacophoric groups. 

The match-search algorithm described above works well for similar Feature Trees of equal sizes or if one tree is fully contained in the other tree. However, as the algorithm cannot generate inner-NIL matches, variable linker regions between pharmacophoric groups cannot be modeled (see Fig. 4.5). 

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