Pharmacophore three-point pharmacophoric feature

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 . 

As shown in this review, the complexity of pharmacophores can range from very simple objects (two- or three-point pharmacophores) to more sophisticated objects by the addition of more pharmacophoric features, different types of geometric constraints, shape, or excluded regions information. 2D (substructure) as well as ID (relational data) information can also be added to a 3D pharmacophore. The nature of the pharmacophoric points (feature vs. substructure) will directly affect the overall performance of a database search. In general, an overspecification of the pharmacophoric points will result in hit lists with limited structural diversity. However, the use of pharmacophores is an efficient procedure since it eliminates quickly molecules that do not possess the required features. Unfortunately, all the retrieved hits are not always active as expected since the presence of the pharmacophoric groups is only one of the multiple components that account for the activity of a molecule. Other properties (physicochemical, ADME, and toxicological properties) are other components of the multidimensional approach that is used to turn a hit into a drug. 

A limitation of the three-point pharmacophore is that it is planar and, hence, has limited ability to describe shape and chirality. Recently, there has been interest in four-point pharmacophores, which are based on four features and their associated distances. Four-point pharmacophores provide increased resolution over three-point pharmacophores and can provide a better representation of shape and chirality, which is important in ligand receptor interactions [21]. However, the number of potential pharmacophores increases enormously in going from three-point to four-point pharmacophores. For example, when distances are divided into seven bins and there are six features, then there are over 9000 possible three-point pharmacophores and 2.3 million four-point pharmacophores [19]. 

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