2-Point pharmacophores

Finally, 3D pharmacophores can be used to provide a naturally partitioned space. By com bining the pharmacophore keys of a set of molecules one can determine how many of th potential 3- or 4- point pharmacophores are accessible to the set and easily identify thos which are not represented. This use of pharmacophores is the basis of a method namei Pharmacophore-Derived Queries (PDQ) [Pickett et al. 1996]. One feature of this particula method is that most molecules will occupy more than one cell (as nearly all molecules wil contain more than one 3-point pharmacophore due to the functionality present an( conformational flexibility). This contrasts with the usual situation, wherein each molecul occupies just one cell. 

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, J.S. and Cheney, D.L. Library design and virtual screening using multiple 4-point pharmacophore fingerprints. Pac. Symp. Biocomput. 1999, 4, 456-467. 

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 3. 3- and 4-point pharmacophores for an endothelin antagonist (6 features/point). 

The 3-point and 4-point pharmacophore methods can be used to analyse and compare different sets of compounds and databases. Figure 7 illustrates the 4-point pharmacophores for the MDDR database [25], the Available Chemical Directory (ACD) [25], a company registry database and a set of combinatorial libraries reported by Mason and co-workers [7, 11, 13]. Previous studies [3] had shown the increase in resolution possible using 4-point instead of 3-point pharmacophores. 

The multiple potential pharmacophore method, used in an absolute or relative sense, provides a powerful new tool for 3D similarity studies. As an example, two endothelin receptor antagonists with about 20 nM activity as antagonists of the ETA receptor were compared [21], Figure 9 shows the numbers of potential 4-point pharmacophores and overlapping pharmacophores. The two compounds have very low 2D similarity, but have significant overlap of their 4-point potential pharmacophores, illustrating the power of the method to find similarity between compounds with similar biological activities. 

Figure 10. The numbers of potential 4-point pharmacophores calculated on the basis of complementary site-points placed in the active sites of thrombin, factor Xa, and trypsin, and number of overlapping pharmacophores (pair-wise and for all 3 serine protease sites).

The use of relative similarity and diversity methods can add powerful new methods for design and analysis. The multiple potential pharmacophore method has been described, and its application to practical design problems discussed. These studies highlight the importance of 4-point pharmacophores and the use of special centres to focus diversity studies. 

J.S. Mason and D.L. Cheney, Library Design and Virtual Screening Using Multiple 4-Point Pharmacophore Fingerprints, Pacific Symposium on Biocomputing, 2000, 5, 573-584. 

FLAP 4-Point Pharmacophore Fingerprints from GRID... 

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