Pharmacophore method extensions

A powerful extension to the potential pharmacophore method has been developed, in which one of the points is forced to contain a special pharmacophore feature, as illustrated in figure 4. All the potential pharmacophores in the pharmacophore key must contain this feature, thus making it possible to reference the pharmacophoric shapes of the molecule relative to the special feature. This gives an internally referenced or relative measure of molecular similarity/diversity. The special feature can be assigned to any atom-type or site-point, or to special dummy atoms, such as those added as centroids of privileged substructures [7, 10]. With one of the points being reserved for this special feature, it would seem even more necessary to use the 4-point definition to capture enough of the... 

The development of 3D pharmacophore methods has spawned a new type of descriptor, the pharmacophore key. This is an extension of the binary keys used to facilitate 3D database... 

In this section, we describe the application of the GBPM method to different selected complexes. The resulting pharmacophore models have been tested extensively for their capacity to retrieve known ligands for the target. The application examples were selected to be representative of a certain type of molecular interaction, including protein-protein, and DNA-ligand interactions. More application examples will be described elsewhere [13]. 

An extension of the method that enables the steric shape of a protein site to be used as an additional constraint in the comparison of multiple potential pharmacophores of a protein site with a ligand has been developed, and is being commercialised as the DiR module of Chem-X. The method is equivalent to simultaneous 3D-database searching using multiple 3D pharmacophoric queries and steric constraints the advantage is that only one conformational sampling is necessary. 

Simon and his coworkers have developed (426) a quantitative 3D-QSAR approach, the minimal steric (topologic) difference (MTD) approach. Oprea et al. (452) compared MTD and CoMFA on affinity of steroids for their binding proteins and found similar results. Snyder and colleagues (453) developed an automated method for pharmacophore extraction that can provide a clear-cut distinction between agonist and antagonist pharmacophores. Klopman (404,454) developed a procedure for the automatic detection of common molecular structural features present in a training set of compounds. This has been used to produce candidate pharmacophores for a set of antiulcer compounds (404). Extensions (454)of this approach allow differentiation between substructures responsible for activity and those that modulate the activity. 

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