Specific pharmacophore

Fig. 7.2 Informative design - asking the right question The most efficient means for a player to guess the correct number from 1 to 16 is a divide and conquer" strategy. However, this requires that the player ask questions in sequence and wait for an answer before asking the next. Informative design asks specific questions so that when they are answered simultaneously, the player is led to the answer. In this example, the questions are compounds either possessing (denoted by 1) or lacking (denoted by 0) a specific pharmacophore. Once the compounds are assayed, a single outcome is found to be consistent with activities and the corresponding pharmacophore is found.

The PHARM specification signifies that a specific atom type must be present at a precise xyz location in the active site. This is useful when designing ligands that must complement a specific pharmacophoric receptor group. 

The unmodified pyridine ring, in contrast to imidazole or imidazoline rings, is seldom associated with any specific pharmacophoric activity. It does, however, appear in a number of therapeutic agents due to the fact that benzene rings in biologically active compounds can often be replaced by pyridines in spite of the presence of the basic nitrogen atom. The relatively small number of pyridines discussed below thus do not reflect the frequency of their occurrence in therapeutic agents instead, examples have been selected that illustrate some facet of pyridine chemistry. 

The advent of combinatorial techniques and solid phase organic synthesis may lead to preparation of large numbers of structurally related molecules in short periods of time. This is important especially for the optimization of lead structures in the pharmaceutical industry [40]. It is now well established and documented that the combinatorial technology and solid phase techniques could offer sufficient latitude for preparation of corresponding chemical libraries with broad structural diversity. The diverse potentiality of (3-lactam moiety as specific pharmacophores and scaffolds has attracted ample interests from pharmaceutical industries for the synthetic methods based on polymer-supported techniques. 

Not only is it possible to identify combinations of interactions that discriminate between the two families, but it is also possible to discriminate certain members within a family. Within family 2, interactions k and q are unique to the binding site from 1 dad. Within family 1, the binding site from lphk has a unique interaction, labelled a , and the binding site from lpfk has f and both as unique interactions. Given that interactions f and f have the highest priority, they can clearly act as principal foci for lpfk-specific pharmacophore design. Interaction f corresponds to a [T-... 

Postprocessing steps of hits may include refinement of placement using MD techniques, specific pharmacophore-based filters that penalize certain features, such as unformed hy-... 

This particular family is composed of three specifically designated carbon/sulfur distance motifs as specific pharmacophores with increased level of lipophilicity, as compared to two previous analogs depicted in Schemes 8 and 9. 

It is probable that the largest number of medicinally directed semi-synthetic agents ever produced containing a specific pharmacophore, the -lactam ring, are the penicillins, cephalosporins and mono-bactams. To these must also be added the synthetic cephems and cephams and the many variations upon those basic themes. Although current figures are not available, it was estimated in 1980 that over 10000 variations on the basic penicillin structure had been made and assayed for their ability to inhibit microbial growth (Hoover, J.R.E., personal communication). 

Interestingly, a comparison between the specific pharmacophore and the binding-site hypotheses vividly establishes the fact that the latter is definitely more acceptable and plausible physiochemically due to the fact that the ensuing overlap of the functional moieties in the process of binding to a receptor is found to be more restrictive than anticipating that the particular site does remain more or less fixed when getting bound to difierent ligands. 

Clicking on the info button opens a window where we can choose the specific pharmacophore features as required for the study by selecting and deselecting the boxes. Each ligand can be visualized for analyzing its features (Figs. 4.82 and 4.83). 

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