4-Point pharmacophores molecular similarity methods

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. 

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 long awaited validation study for the XED method for molecular similarity has been published.69 Molecules are described using the maxima and minima in the electrostatic and steric fields around the molecule. These points form a pharmacophore, and so can be used to search databases for alternative chemotypes. As the representation is sparse, several conformations per molecule can be considered. A new chemotype with nanomolar potency for CCK2 and improved excretion properties was found. This is a good concrete example of the power of the XED representation. Other than that, this area has been comparatively quiet, awaiting more developments in alignment methods, as discussed in the next section (Table 1). 

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