Four-point pharmacophores

Mason, J.S. and Beno, B.R. Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints simultaneous optimization and structure-based diversity. /. Mol. 

Fig. 15.25 Partial display of virtual screen of conformational ensemble of " 75 000 structure library based on multiple templates. A display of fitness scores to a three-point pharmacophore model provides initial signs of similarity of a library design to that model. Subsequent virtual screening against a more stringent four-point pharmacophore model further highlights potentially useful library designs.

The receptor relevance of BCUT descriptors has inspired several groups to apply them in conjunction with other methods. Beno and Mason reported the use of simulated annealing to optimize library design using BCUT chemistry space and four-point pharmacophores concurrently (33) and the use of chemistry spaces in conjunction with property profiles (52). The application of such composite methods to target class library design is readily apparent. Pirard and Pickett reported the application of the chemometric method, partial least squares discriminant analysis, with BCUT descriptors to successfully classify ATP-site-directed kinase inhibitors active against five different protein kinases... 

Three-point pharmacophores have traditionally been used for many applications but have recently been more and more replaced by four-point pharmacophores (Mason et al. 1999), which increases the complexity of the search but also the resolution of the pharmacophore analysis. This is the case because the additional point increases the total number of inter-point distances from three for a three-point pharmacophore to six for a four-point pharmacophore. Pharmacophore searching is further refined by assigning alternative features to each point (e.g., hydrogen bond acceptors, donors, or charged groups) and ranges to inter-point distances (rather than an exact distance). For example, five different features (e.g., atom types or groups) may be permitted for each point... 

The extension to four-point pharmacophores enables chirality to be handled and enables some elements of volume/shape linked to... 

Figure 5.4. Three- and four-point (triplet/quartet) pharmacophore fingerprint creation. Assignment is often binary (on or off), although a count can be kept, and has been used in more recent studies. The large difference in bin numbers between three- and four-point pharmacophores provides additional shape information, thus increasing molecular separation in similarity and diversity studies.

Shape. Pharmacophores capture the key features of intermolecular interactions. However, they do not explicitly capture the shape and volume of the ligand, even if this is crudely implied by the largest four-point pharmacophore exhibited, and the totality of potential pharmacophores exhibited across a range of conformations encodes shape fragments. Hahn (47) has described a method for three-dimensional shape-based searching implemented in the Catalyst program. Seven... 

Figure 5.7. Comparisons of the 3D four-point pharmacophore fingerprints exhibited by several sets [MDDR database of 62,000 biologically active compounds, a corporate registry database of 100,000 compormds used for screening, 100,000 compounds from combinatorial libraries (from a four-com-poilent Ugi condensation reaction), and 14,000 compound random subsets (MDDR, corporate) or indlividual libraries]. The four-point potential pharmacophores were calculated using 10 distance range bins and the standard six pharmacophore features.

The relative merits of two-, three- and four-point pharmacophore descriptors for different applications is an area of ongoing study (37, 83). Figure 5.9 shows some structurally diverse endothelin antagonists that exhibit low 2D similarity, but maintain significant overlap of their four-point pharmacophore fingerprints (37a). 

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