Feature 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. 

The pharmacophore build-up procedure is similar to that in Catalyst HipHop. Two-point pharmacophores characterized by the two features and a binned dis-... 

LigandScout pharmacophores solely consist of chemical features classified as layers 3 and 4 (Table 6.2). Visualization mainly distinguishes between point and vector features point features (layer 4) are defined as a center with a tolerance this group encompasses hydrophobic, positively ionizable and negatively ioniz-able areas, in addition to excluded volume spheres. Hydrogen donors, acceptors and donor-acceptor pairs belong to the vector features group. 

The binding models of the 15 ligands were used to derive a 7-point pharmacophore connecting the different structural classes of CSI, based on consistent structural features and recurring tubulin-ligand interactions. As shown in Fig. 3a, the common... 

Fig. 3a,b Common seven-point pharmacophore for CSI. a Pharmacophoric points within the colchicine binding site together with the most important residues involved in interactions with them, b Colchicine is able to map five features, while podophyllotoxin (c) matches six points. The figure has been generated from the IS AO and 1SA1 structures of PDB, using the information provided by the paper of Nguyen and co-workers [38]... 

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... 

A similar approach based on pharmacophore keys is used in the ChemDiverse software [54]. Here, the key is based on three-point pharmacophores generated for seven features over 32 distances. This gives over 2 million theoretical combinations however, this number can be reduced by geometric and symmetry considerations. The key marks the presence or absence of the pharmacophores within the collection and because of its size it is normally used to represent a whole library of compounds, although in principle it can also be used to represent a single compound. 

The ChemDiverse method uses predefined ranges for measuring the distances between the points (pharmacophoric features) distances are calculated exactly but stored using this binning scheme, with each distance represented by the bin into whose range it falls. Each pharmacophore for the 4-point method needs six distances to be characterised (to form a tetrahedron), whereas three distances are needed for each 3-point pharmacophore (triangle). All the combinations of features and distances, combined for all the evaluated conformers, are stored in a pharmacophore key . 

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

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