4-Point pharmacophores privileged

Mason JS, Morize 1, Menard PR, Cheney DL, Hulme C, Labaudiniere RF. New 4-point pharmacophore method for molecular similarity and diversity applications Overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. I Med Chem 1999 42 3251-64. 

Mason JS, Morize I, Menard PR, Cheney DL, Huhne C, Labaudiniere RF. (1999) New 4-Point Pharmacophore Method for Molecular Similarity and Diversity Appheations Overview of the Method and Applications, including a Novel Approach to the Design of Combinatorial Libraries Containing Privileged Substructures. J. Med. Chem. 42 3251-3264. 

Figure 5.19. Example of a "privileged" four-point pharmacophore. Here biphenyl tetrazole, a substructure seen in a number of GPCR inhibitors, is specifically defined as a pharmacophore feature, using a centroid dummy atom. Only pharmacophores that include this type are included in the fingerprint, thus providing a relative measure of diversity/similarity with respect to the privileged feature.

Total 4-point pharmacophores 3601 -with "privileged" feature 1569 (using 10 (Hstance ranges)... 

To account for the privileged substructures, one of the four pharmacophore points is forced to be a feature associated with the privileged substructure. In practice, this feature is a dummy atom deflned as the centroid of the substructure. Then, privileged pharmacophore keys are 4-point pharmacophore keys, where only pharmacophores including the dummy atom representing the substructure of interest are stored. 

Mason et al. [21] have adapted the four-point pharmacophore methods to take account of privileged substructures. Privileged substructures are substructures able to provide high-affinity ligands for more than one type of receptor or enzyme. One of the four pharmacophoric features is forced to be a special feature associated with the privileged substructure itself. For example, a dummy atom is assigned as the centroid of the substructure and all pharmacophoric patterns must include this dummy atom. Thus, similarity and diversity measures can be focused around the privileged substructure. 

When used for relative similarity and diversity, only potential pharmacophores that contain the defined special centre-type are used. The frame of reference for similarity/diversity studies is thus changed to one that is focused on the feature of interest distances are now measured relative to this special centre. For example, the special centre could be the centroid of a substructure [10] such as biphenyl tetrazole or diphenylmethane, enabling the calculation and comparison of all 3D pharmacophoric shapes that contain this substructure the substructure is said to be privileged . For structure-based design, the potential pharmacophores in a site can be restricted to those that contain a specific site point (e.g. in a pocket, or at the entrance to a pocket). In the context of combinatorial library design, the relative measure can be those pharmacophoric shapes that contain a special site-point that represents where the attachment point for a reagent would be. In figure 1, the special point would be centre-type number 3, which can be reserved for this purpose. 

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... 

Figure 5. Example of a relative pharmacophore, with the privileged biphenyltetrazole substructure as the special point (shown as a square), and the connections to the other centres (dotted lines).

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