Library design privileged substructures

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. 

Savchuk, N.P., Tkachenko, S.E., and Baiakin, K.V. Rational design of GPCR-specific combinatorial libraries based on the concept of privileged substructures. In Chemoinformatics in... 

Rational Design of CPCR-specific Combinational Libraries Based on the Concept of Privileged Substructures... 

Privileged Substructures for Target Class Library Design... 

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. 

Figure 5.22. Example of pharmacophore feature assignments involving the biphenyl tetrazole "privileged" substructure and the total four-point potential pharmacophores calculated for a GPCR antagonist. Note that just the subset (40%) of the total pharmacophores that contained the "privileged" substructure was used for the library design.

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