Pharmacophore four-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... 

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.

Figure 5.8. Example of privileged four-point pharmaeophores, either ereated from a ligand using a particular feature (e.g., the centroid of a "privileged" substructure) or complementary to a protein site using a site point or attachment point of a docked scaffold. Only pharmacophores that include this special feature are included in the fingerprint, thus providing a relative measure of diversity 1 similarity with respect to the privileged feature.

Figure 5.22. Example of pharmacophore feature assignments involving the biphenyl tetrazole "privileged" substructure and the total four-point potential pharmacophores calculated for a GPCR antagonist. Note that just the subset (40%) of the total pharmacophores that contained the "privileged" substructure was used for the library design.

Applying supervised machine learning techniques, Li et al. [66] proposed a model that differentiates substrates from nonsubstrates of P-gp based on a simple tree using nine distinct pharmacophores. Four-point 3D pharmacophores were employed to increase the amount of shape information and resolution and possessed the ability to distinguish chirality. Relevant features were hydrogen-bond acceptors, hydrophobic-ity indices, and a cationic charge. 

Several researchers have exploited the wealth of crystal structures of kinase inhibitor complexes to build protein-based pharmacophores for this target class (20). Aronov and Murcko (21) considered the crystal structures of four promiscuous kinase inhibitors, i.e., inhibitors with an affinity of at least 2 pM on five representative kinases. After aligning the structures of the four proteins, they assigned pharmacophoric features to the bound inhibitors, which led to the identification of five clusters of pharmacophoric features. These served to define a five point pharmacophore for kinase frequent hitters (Fig. la). This pharmacophore could discriminate frequent hitters from selective kinase inhibitors. Recently, McGregor (22) aligned 220 kinase crystal structures from the PDB and assigned one of seven possible pharmacophoric types to each atom of the bound ligands. 

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]. 

Mason et al. [21] have adapted the four-point pharmacophore methods to take account of privileged substructures. Privileged substructures are substructures able to provide high-affinity ligands for more than one type of receptor or enzyme. One of the four pharmacophoric features is forced to be a special feature associated with the privileged substructure itself. For example, a dummy atom is assigned as the centroid of the substructure and all pharmacophoric patterns must include this dummy atom. Thus, similarity and diversity measures can be focused around the privileged substructure. 

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